Sensitivity of mice to lipopolysaccharide is increased by a high saturated fat and cholesterol diet

<p>Abstract</p> <p>Background</p> <p>It was hypothesized that a pro-atherogenic, high saturated fat and cholesterol diet (HCD) would increase the inflammatory response to <it>E. coli </it>endotoxin (LPS) and increase its concentration in plasma after administration to mice.</p> <p>Methods</p> <p>C57Bl/6 mice were fed a HCD or a control diet (CD) for 4 weeks, and then treated with saline, 0.5, 1 or 2 mg LPS/kg, ip. Liver injury (alanine:2-oxoglutarate aminotransferase and aspartate aminotransferase, collagen staining), circulating cytokines (tumor necrosis factor-α, interleukin-6 and interferon-γ), factors that can bind LPS (serum amyloid A, apolipoprotein A1, LPS binding protein, and CD14), and plasma levels of LPS were measured. The hepatic response was assessed by measuring vascular cell adhesion molecule (VCAM)-1, inducible nitric oxide synthase (iNOS) and signal transducer and activator of transcription-1 proteins, and VCAM-1 and iNOS mRNAs. Hepatic mRNA encoding the LPS receptor, Toll like receptor 4, was also determined.</p> <p>Results</p> <p>Two mg LPS/kg killed 100% of mice fed HCD within 5 d, while no mice fed CD died. All mice treated with 0 to 1 mg LPS/kg survived 24 h. HCD increased plasma alanine:2-oxoglutarate aminotransferase and aspartate aminotransferase, and the enzymes were increased more by LPS in HCD than CD mice. Induction of plasma tumor necrosis factor-α, interleukin-6, and interferon-γ by LPS was greater with HCD than CD. Hepatic VCAM-1 and iNOS protein and mRNA were induced by LPS more in mice fed HCD than CD. Tyrosine phosphorylation of signal transducer and activator of transcription-1 caused by LPS was prolonged in HCD compared with CD mice. Despite the hepatic effects of HCD, diet had no effect on the LPS plasma concentration-time profile. HCD alone did not affect circulating levels of plasma apolipoprotein A1 or LPS binding protein. However, plasma concentrations of serum amyloid A and CD14, and hepatic toll-like receptor-4 mRNA were increased in mice fed HCD.</p> <p>Conclusion</p> <p>HCD increased the sensitivity of mice to LPS without affecting its plasma level. Although increased serum amyloid A and CD14 in the circulation may inhibit LPS actions, their overexpression, along with hepatic toll-like receptor-4 or other factors, may contribute to the heightened sensitivity to LPS.</p

Protein Never in Mitosis Gene A Interacting-1 regulates calpain activity and the degradation of cyclooxygenase-2 in endothelial cells

© 2009 Liu et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution Licens

Implicit Regularization and Convergence for Weight Normalization

Normalization methods such as batch [Ioffe and Szegedy, 2015], weight [Salimansand Kingma, 2016], instance [Ulyanov et al., 2016], and layer normalization [Baet al., 2016] have been widely used in modern machine learning. Here, we study the weight normalization (WN) method [Salimans and Kingma, 2016] and a variant called reparametrized projected gradient descent (rPGD) for overparametrized least-squares regression. WN and rPGD reparametrize the weights with a scale g and a unit vector w and thus the objective function becomes non-convex. We show that this non-convex formulation has beneficial regularization effects compared to gradient descent on the original objective. These methods adaptively regularize the weights and converge close to the minimum l2 norm solution, even for initializations far from zero. For certain stepsizes of g and w , we show that they can converge close to the minimum norm solution. This is different from the behavior of gradient descent, which converges to the minimum norm solution only when started at a point in the range space of the feature matrix, and is thus more sensitive to initialization.Comment: NeurIPS 202

Pathological Role of Peptidyl-Prolyl Isomerase Pin1 in the Disruption of Synaptic Plasticity in Alzheimer’s Disease

Synaptic loss is the structural basis for memory impairment in Alzheimer’s disease (AD). While the underlying pathological mechanism remains elusive, it is known that misfolded proteins accumulate as β-amyloid (Aβ) plaques and hyperphosphorylated Tau tangles decades before the onset of clinical disease. The loss of Pin1 facilitates the formation of these misfolded proteins in AD. Pin1 protein controls cell-cycle progression and determines the fate of proteins by the ubiquitin proteasome system. The activity of the ubiquitin proteasome system directly affects the functional and structural plasticity of the synapse. We localized Pin1 to dendritic rafts and postsynaptic density (PSD) and found the pathological loss of Pin1 within the synapses of AD brain cortical tissues. The loss of Pin1 activity may alter the ubiquitin-regulated modification of PSD proteins and decrease levels of Shank protein, resulting in aberrant synaptic structure. The loss of Pin1 activity, induced by oxidative stress, may also render neurons more susceptible to the toxicity of oligomers of Aβ and to excitation, thereby inhibiting NMDA receptor-mediated synaptic plasticity and exacerbating NMDA receptor-mediated synaptic degeneration. These results suggest that loss of Pin1 activity could lead to the loss of synaptic plasticity in the development of AD

Pharmacological targeting of STK19 inhibits oncogenic NRAS driven melanomagenesis

黑色素瘤是由黑色素细胞恶性转化产生的恶性程度极高的皮肤癌，含有NRAS激活突变的黑色素瘤约占20-30%，但至今还未有靶向NRAS的有效黑色素瘤治疗方案。针对这一难题，波士顿大学医学中心崔儒涛教授、厦门大学生命科学学院邓贤明教授、复旦大学附属肿瘤医院王鹏教授组成的联合研究团队利用激酶组siRNA文库筛选发现新颖的丝/苏氨酸激酶STK19是NRAS的上游激活子，进一步分子机制研究揭示STK19通过磷酸化NRAS的89位丝氨酸（S89）促进了NRAS介导的黑色素细胞恶性转化。该研究揭示了一种经由新颖激酶STK19调控NRAS突变黑色素瘤的分子机制，验证了STK19有望作为NRAS介导的黑色素瘤的有效靶标，为发展新的黑色素瘤靶向药物提供了先导化合物，同时也为发展其它素有“癌基因之王---RAS”驱动的相关肿瘤靶向药物发展提供了新思路。该论文由波士顿大学医学中心、厦门大学生命科学学院、复旦大学附属肿瘤医院等单位合作完成，共同第一作者厦门大学生命科学学院博士生张婷负责了该系列化合物的设计、合成与优化，崔儒涛教授、邓贤明教授和王鹏教授为共同通讯作者。【Abstract】Activating mutations in NRAS account for 20-30% of melanoma, but despite decades of research and in contrast to BRAF, no effective anti-NRAS therapies have been forthcoming. Here we identify a previously uncharacterized serine/threonine kinase STK19 as a novel NRAS activator. STK19 phosphorylates NRAS to enhance its binding to its downstream effectors and promotes oncogenic NRAS-mediated melanocyte malignant transformation. A recurrent D89N substitution in STK19 whose alterations were identified in 25% of human melanomas represents a gain-of-function mutation that interacts better with NRAS to enhance melanocyte transformation. STK19 D89N knockin leads to skin hyperpigmentation and promotes NRAS Q61R -driven melanomagenesis in vivo. Finally, we developed ZT-12-037-01 (1a) as a specific STK19-targeted inhibitor and showed that it effectively blocks oncogenic NRAS-driven melanocyte malignant transformation and melanoma growth in vitro and in vivo. Together, our findings provide a new and viable therapeutic strategy for melanomas harboring NRAS mutations.We thank Drs. Norman Sharpless and David Fisher for kindly providing the loxP/STOP/loxP NRAS Q61R knockin (LSL-NRAS Q61R ) mice. We thank Dr. Anurag Singh for kindly sharing cell lines. We also thank Drs. X. Shirley Liu, Tao Wang, Wantao Chen, Dali Liu, Chunxiao Xu, Jianming Zhang and Junrong Zou for discussion and assistance. This work was supported by grants from Boston University (to R.C.), the National Key R&D Program and the National Natural Science Foundation of China (No. 2017YFA0504504, 2016YFA0502001, 81422045, U1405223 and 81661138005 to X.D.), the Fundamental Research Funds for the Central Universities of China (No. 20720160064 to X.D.), and the Program of Introducing Talents of Discipline to Universities (111 Project, B12001).该研究得到了科技部重点研发计划、国家自然科学基金委和中央高校基本科研业务费等的资助