Hepatic Circadian-Clock System Altered by Insulin Resistance,Diabetes and Insulin Sensitizer in Mice

Circadian rhythms are intrinsic rhythms that are coordinated with the rotation of the Earth and are also generated by a set of circadian-clock genes at the intracellular level. Growing evidence suggests a strong link between circadian rhythms and energy metabolism; however, the fundamental mechanisms remain unclear. In the present study, neonatal streptozotocin (STZ)-treated mice were used to model the molecular and physiological progress from insulin resistance to diabetes. Two-day-old male C57BL/6 mice received a single injection of STZ and were tested for non-obese, hyperglycemic and hyperinsulinemic conditions in the early stage, insulin resistance in the middle stage, and diabetes in the late stage. Gene expression levels of the hepatic circadian-clock system were examined by real-time quantitative PCR. Most of the components of the hepatic circadian-clock gene expression system, such as the mRNAs of Bmal1 (brain and muscle Arnt-like protein-1), Per2 (period 2) and Cry1 (cryptochrome 1), were elevated, and circadian patterns were retained in the early and middle stages of insulin-resistant conditions. The insulin sensitizer, rosiglitazone, returns the physiological and molecular changes associated with the diabetic phenotype to normal levels through peroxisome proliferator-activated receptor γ (PPARγ) rather than PPARα. Early and chronic treatment with rosiglitazone has been shown to be effective to counter the diabetic condition. Over time, this effect acts to attenuate the increased gene expression levels of the hepatic circadian-clock system and delay the severity of diabetic conditions. Together, these results support an essential role for the hepatic circadian-clock system in the coordinated regulation and/or response of metabolic pathways.     

Comparative Validity and Reproducibility Study of Various Landmark-Oriented Reference Planes in 3-Dimensional Computed Tomographic Analysis for Patients Receiving Orthognathic Surgery

BackgroundThree-dimensional computed tomographic imaging has become popular in clinical evaluation, treatment planning, surgical simulation, and outcome assessment for maxillofacial intervention. The purposes of this study were to investigate whether there is any correlation among landmark-based horizontal reference planes and to validate the reproducibility and reliability of landmark identification.ResultsA total of 30 patients with facial deformity and malocclusion—10 patients with facial symmetry, 10 patients with facial asymmetry, and 10 patients with cleft lip and palate—were recruited. Comparing the differences among the 5 reference planes showed no statistically significant difference among all patient groups. Regarding intraobserver reproducibility, the mean differences in the 3 coordinates varied from 0 to 0.35 mm, with correlation coefficients between 0.96 and 1.0, showing high correlation between repeated tests. Regarding interobserver reliability, the mean differences among the 3 coordinates varied from 0 to 0.47 mm, with correlation coefficients between 0.88 and 1.0, exhibiting high correlation between the different examiners.ConclusionsThe 5 horizontal reference planes were reliable and comparable for 3D craniomaxillofacial analysis. These reference planes were useful in standardizing the orientation of 3D skull models.     

Spatial and Functional Heterogeneities Shape Collective Behavior of Tumor-Immune Networks

Tumor growth involves a dynamic interplay between cancer cells and host cells, which collectively form a tumor microenvironmental network that either suppresses or promotes tumor growth under different conditions. The transition from tumor suppression to tumor promotion is mediated by a tumor-induced shift in the local immune state, and despite the clinical challenge this shift poses, little is known about how such dysfunctional immune states are initiated. Clinical and experimental observations have indicated that differences in both the composition and spatial distribution of different cell types and/or signaling molecules within the tumor microenvironment can strongly impact tumor pathogenesis and ultimately patient prognosis. How such “functional” and “spatial” heterogeneities confer such effects, however, is not known. To investigate these phenomena at a level currently inaccessible by direct observation, we developed a computational model of a nascent metastatic tumor capturing salient features of known tumor-immune interactions that faithfully recapitulates key features of existing experimental observations. Surprisingly, over a wide range of model formulations, we observed that heterogeneity in both spatial organization and cell phenotype drove the emergence of immunosuppressive network states. We determined that this observation is general and robust to parameter choice by developing a systems-level sensitivity analysis technique, and we extended this analysis to generate other parameter-independent, experimentally testable hypotheses. Lastly, we leveraged this model as an in silico test bed to evaluate potential strategies for engineering cell-based therapies to overcome tumor associated immune dysfunction and thereby identified modes of immune modulation predicted to be most effective. Collectively, this work establishes a new integrated framework for investigating and modulating tumor-immune networks and provides insights into how such interactions may shape early stages of tumor formation.     

噪声和二硫化碳对大鼠外膝体神经元光反应的影响及其联合效应

目的：观察噪声或二硫化碳（CS2）暴露对大鼠外侧膝状体（LGB）神经元光反应的影响及二者的联合效应。方法：脉冲噪声刺激和光栅刺激由计算机控制输出,CS2通过皮下注射,运用电生理学方法记录LGB神经元电活动。结果：噪声暴露后有21％的神经元光反应被抑制,当噪声持续时,抑制程度有增强的趋势,呈现出剂量效应关系。不同剂量的CS2暴露,神经元受到不同程度的抑制,亦呈剂量一效应关系。噪声和CS2同时作用时,呈一定的协同作用。结论：噪声或者CS2的单独作用可明显抑制外膝体神经元的光反应,在共同作用时存在联合效应,主要表现为协同效应。     

腺病毒介导的HIF-1α基因在缺血心肌中的表达

 研究腺病毒介导的低氧诱导因子=1α(HIF=1α)在急性心肌梗死(AMI)后缺血心肌中的表达变化.建立兔AMI模型,随机分为4组,分别心肌内注入腺病毒介导的HIF-1α基因(Ad-HIF-1α)、不含HIF-1α基因腺病毒颗粒(Ad--Blank)、HIF-1α核酶基因(Rz-HIF-1α),假手术组(Sham)为对照.RT-PCR和免疫组化方法分别检测HIF-1α及下游基因VEGF的mRNA和蛋白在不同时间点的表达.结果显示,AMI后1 d, HIF-1α、VEGF的mRNA和蛋白表达开始升高,7 d 达高峰,14 d、28 d逐渐下降,56 d时HIF-1αmRNA和蛋白无表达,而VEGF mRNA和蛋白仍有表达. 因此, 腺病毒介导的HIF-1α基因在缺血心肌能被有效转染并激活,其表达的时间窗为心肌缺血急性期至亚急性期.HIF-1α核酶基因能抑制HIF-1α及其下游基因的表达.     

Prenatal diagnosis and genetic counseling of mucopolysaccharidosis type II (Hunter syndrome)

We present prenatal diagnosis of mucopolysaccharidosis type II (MPS II) (Hunter syndrome) and demonstrate marked mucopolysaccharide deposition in multiple vital organs in a 22-gestational-week affected fetus. Level II ultrasound showed cardiomegaly and hepatomegaly. Histological examinations of the fetal vital organs manifested marked mucopolysaccharide deposition. We suggest that any therapeutic approach and counseling for prenatally diagnosed MPS II should consider the early signs of in utero marked mucopolysaccharide storage.     

SAR of a novel 'Anthranilamide Like' series of VEGFR-2, multi protein kinase inhibitors for the treatment of cancer

Novel anthranilamides were surprisingly found to exert additional activity on B-RAF. Corresponding thiophene, pyrazole, and thiazole core analogs were prepared as VEGFR-2 inhibitors with c-KIT, and B-RAF activity. Compounds in the phenyl, thiophene, and thiazole series are in vivo active.     

A Stochastic Model of Smoking Behavior Under a Cessation Program

A stochastic model describing the movements, resulting from a smoking cessation program, of a cohort of individuals from the smoking to the non‐smoking compartment is proposed. The distribution and first two moments of the number of smokers are derived.