Sphingosine 1-phosphate, a specific endogenous signaling molecule controlling cell motility and tumor cell invasiveness.

Sphingosine 1-phosphate (Sph-1-P), the initial product of Sph degradation by Sph kinase, was shown to be a strong inhibitor of cell motility and phagokinesis of B16 melanoma and other types of cells at 10-100 nM concentration. It also inhibited "chemoinvasion" of tumor cells through a thick layer of Matrigel on a filter membrane. Such inhibitory effects were produced minimally or not at all by Sph, N-methyl derivatives of Sph, or other related sphingolipids and phospholipids. Sph-1-P did not inhibit cell proliferation or protein kinase C (PKC) activity, in contrast to Sph and N-methyl-Sph, which inhibit PKC activity and cell growth in general. Radiolabeled [3H]Sph and [14C]N-methyl-Sph were rapidly incorporated into B16 melanoma cells. However, [14C]N-methyl-Sph was not metabolically converted into other compounds, whereas [3H]Sph was efficiently converted within 10 min to Sph-1-P, followed by conversion to other sphingolipids and phospholipids. The inhibitory effect of Sph-1-P on cell motility and tumor cell invasiveness could be a specific phenomenon independent of PKC and other known transmembrane signaling mechanisms, based on an unknown mechanism. It may directly affect organizational assembly of actin filaments. Since exogenous Sph is rapidly converted into Sph-1-P, some reported effects of Sph may be ascribable to such conversion.     

MicroRNA-200a inhibits epithelial-mesenchymal transition in human hepatocellular carcinoma cell line

Objective: Our study investigated the role of microRNA (miR)-200a and its molecular targets in hepatocellular carcinoma (HCC) cells. Methods: An inhibitor of miR-200a was transiently transfected into the hepatocellular carcinoma cell line, MHCC-97L. The effect of this transfection on mRNA levels of epithelial-mesenchymal transition (EMT)-related genes was measured by fluorescence-based quantitative real-time polymerase chain reaction (qRT-PCR). Further, protein levels of EMT-related genes, cell proliferation and apoptosis-related markers were assessed by Western blot analysis in these transfected cells. MTT and wound-healing assay were used to evaluate the proliferation and migration of MHCC-97L cells in presence and in absence of miR-200a inhibitor. Results: Compared with miR-NC control group, qRT-PCR results in anti-miR-200a group revealed a significant reduction in the mRNA levels of E-cadherin, with a concomitant increasing in vimentin mRNA level (all P < 0.05). Western blot results showed higher E-cadherin and Caspase-3 protein expressions in anti-miR-200a group compared to miR-NC group (P < 0.05). In addition, vimentin and Ki-67 protein expression was found sharply decreased in anti-miR-200a group compared to miR-NC group (P < 0.05). Consistent with this, wound-healing and MTT assay showed that migration and proliferation capacity of MHCC-97L cells in anti-miR-200a group is significantly increased compared with miR-NC group (both P < 0.05). Conclusion: Our study reveals an important role of miR-200a in inhibiting EMT, proliferation and migration in HCC cells, suggesting the possibility of miR-200a-based therapeutics in HCC.     

Mixed lineage kinase domain-like protein is a prognostic biomarker for cervical squamous cell cancer

Background: The mixed lineage kinase domain-like protein (MLKL) has recently been identified as a key RIP3 (receptor interacting protein 3) downstream component of tumor necrosis factor (TNF)-induced necroptosis. Objective: To evaluate the expression and clinical significance of MLKL in cervical squamous cell carcinoma.Methods: The expression of MLKL in 54 cervical squamous carcinoma samples was detected by immuneohistochemical method. Chi-square, correlation analysis and kaplan-Meier method were used to analyze the data. Results: The MLKL expression in cervical squamous cell carcinoma was higher than that in normal cervical tissues (P = 0.004). The MLKL expression was negatively correlated with histological grade, lymphatic metastasis (P<0.05). Survival analysis showed the low expression of MLKL indicated poor prognosis. Conclusion: MLKL was a prognostic biomarker for cervical squamous cell carcinoma.     

不同表面处理方式对丙烯酸树脂表面性状和粘接强度的影响

目的探讨不同表面处理方式对丙烯酸树脂表面性状和粘接强度的影响。方法制备硅橡胶与丙烯酸树脂构成的重叠联合模型。根据树脂条的不同表面处理方式,将模型随机分为4组:对照组、MMA浸润组、喷砂组、MMA浸润+喷砂组。用扫描电镜观察各组树脂处理后的表面形态变化,用粗糙度仪检测其粗糙度,万能材料试验机测定树脂条和硅橡胶之间的粘接强度。结果 1.电镜观察显示,未经处理的树脂条表面打磨痕迹明显,经过MMA浸润后,表面出现溶解的痕迹,经过喷砂后,表面粗糙凸凹不平;2.粗糙度:喷砂组(3.12±0.02)μm和MMA浸润+喷砂组(3.11±0.01)μm>对照组(0.73±0.01)μm和MMA浸润组(0.71±0.01)μm,且差异有统计学意义(P<0.05);3.粘接强度:MMA浸润+喷砂组(2.34±0.03)MPa>喷砂组(2.02±0.01)MPa>MMA浸润组(1.81±0.02)MPa>对照组(1.50±0.01)MPa,且差异有统计学意义(P<0.05)。结论 MMA单体浸润与喷砂的处理方式可以使丙烯酸树脂表面的形貌发生变化,更有利于硅橡胶与丙烯酸树脂的结合,获到良好的粘接效果,可在临床推广使用。     

Current status of auditory aging and anti‐aging research

The development of presbycusis, or age‐related hearing loss, is determined by a combination of genetic and environmental factors. The auditory periphery exhibits a progressive bilateral, symmetrical reduction of auditory sensitivity to sound from high to low frequencies. The central auditory nervous system shows symptoms of decline in age‐related cognitive abilities, including difficulties in speech discrimination and reduced central auditory processing, ultimately resulting in auditory perceptual abnormalities. The pathophysiological mechanisms of presbycusis include excitotoxicity, oxidative stress, inflammation, aging and oxidative stress‐induced DNA damage that results in apoptosis in the auditory pathway. However, the originating signals that trigger these mechanisms remain unclear. For instance, it is still unknown whether insulin is involved in auditory aging. Auditory aging has preclinical lesions, which manifest as asymptomatic loss of periphery auditory nerves and changes in the plasticity of the central auditory nervous system. Currently, the diagnosis of preclinical, reversible lesions depends on the detection of auditory impairment by functional imaging, and the identification of physiological and molecular biological markers. However, despite recent improvements in the application of these markers, they remain under‐utilized in clinical practice. The application of antisenescent approaches to the prevention of auditory aging has produced inconsistent results. Future research will focus on the identification of markers for the diagnosis of preclinical auditory aging and the development of effective interventions. Geriatr Gerontol Int 2014; 14: 40–53.     

Design,synthesis, and biological evaluation of thieno[3,2‐d]pyrimidine derivatives as potential simplified phosphatidylinositol 3‐kinase alpha inhibitors

A series of thieno[3,2‐d]pyrimidine derivatives as phosphatidylinositol 3‐kinase (PI3K) inhibitors was designed using the combination strategy. The synthesis and biological evaluation of the derivatives demonstrated their potent inhibition of PI3K, culminating in the discovery of 7 and 21 . Determination of a co‐crystal structure of 7 complexed with PI3Kα provided the structural basis for the high enzymatic activity. Furthermore, cellular investigation of compounds 7 and 21 revealed that they efficiently suppressed cancer cell lines proliferation through inhibition of intracellular PI3K/AKT/mammalian target of rapamycin pathway. The results provided potent simplified inhibitors of PI3K with a promising overall profile and a chemical series for further optimization to progress into vivo experiments.     

Perennial grasslands enhance biodiversity and multiple ecosystem services in bioenergy landscapes

Agriculture is being challenged to provide food, and increasingly fuel, for an expanding global population. Producing bioenergy crops on marginal lands—farmland suboptimal for food crops—could help meet energy goals while minimizing competition with food production. However, the ecological costs and benefits of growing bioenergy feedstocks—primarily annual grain crops—on marginal lands have been questioned. Here we show that perennial bioenergy crops provide an alternative to annual grains that increases biodiversity of multiple taxa and sustain a variety of ecosystem functions, promoting the creation of multifunctional agricultural landscapes. We found that switchgrass and prairie plantings harbored significantly greater plant, methanotrophic bacteria, arthropod, and bird diversity than maize. Although biomass production was greater in maize, all other ecosystem services, including methane consumption, pest suppression, pollination, and conservation of grassland birds, were higher in perennial grasslands. Moreover, we found that the linkage between biodiversity and ecosystem services is dependent not only on the choice of bioenergy crop but also on its location relative to other habitats, with local landscape context as important as crop choice in determining provision of some services. Our study suggests that bioenergy policy that supports coordinated land use can diversify agricultural landscapes and sustain multiple critical ecosystem services.In agricultural landscapes, balancing the provisioning of food and energy with maintenance of biodiversity and ecosystem functions is a global challenge. To avoid impacts on food production, attention is increasingly being focused on the potential for marginal lands to support bioenergy production (1). Marginal lands, those suboptimal for food production, may consist of relatively small areas within generally productive landscapes or larger regions where conditions generally limit crop productivity. However, there is increasing recognition that these lands are already performing a variety of useful functions, and their conversion to bioenergy cropping could reduce these services. For example, in the north central United States, rising commodity prices are predicted to bring marginal croplands—including Conservation Reserve Program lands—into annual crop production with negative impacts on wildlife habitat and water quality (2, 3). With 2013 corn plantings at recent record highs (4) and new reports of grassland and wetland conversion to cropland (5, 6), this may be occurring already.An alternative to annual cropping is conversion of marginal croplands to perennial, cellulosic crops for bioenergy. Although current US biofuel production centers on grain ethanol derived from annual monocultures of maize (Zea mays), this situation could change with full implementation of the 2007 US Energy Independence and Security Act (7), which calls for increased production of cellulosic biofuels. In the Midwest United States, perennial grasses and forbs grown on marginal lands could provide up to 25% of national targets for cellulosic biofuel, with substantial greenhouse gas (GHG) benefits (8). Moreover, increasing the area of perennial cover on the landscape is predicted to positively affect a diverse array of organisms and ecological functions (9–11), leading to important synergies that have not yet informed the ongoing bioenergy debate. Here we provide the most comprehensive empirical evaluation of this hypothesis to date, reporting data that elucidate the impacts of different bioenergy cropping systems on a wide variety of organisms and the ecosystem functions they perform.Previous studies have examined the ability of select bioenergy crops to support specific taxa (12) or individual services such as energy production (13) or GHG mitigation (14), without consideration of the tradeoffs or synergies that can arise when considering entire suites of organisms and ecosystem functions. We report on a unique multidisciplinary study of matched sets of organisms and ecosystem services and show that perennial grass energy crops (switchgrass, Panicum virgatum, and mixed prairie plantings) synergistically enhance diversity of a variety of organisms and levels of the services they provide. We further quantify the importance of landscape context on service provisioning, suggesting that policy supporting intentional design of bioenergy landscapes could increase sustainability of both food and energy production.     

Prognostic Value of TIMI Score versus GRACE Score in ST-segment Elevation Myocardial Infarction

Background

The TIMI Score for ST-segment elevation myocardial infarction (STEMI) was created and validated specifically for this clinical scenario, while the GRACE score is generic to any type of acute coronary syndrome.

Objective

Between TIMI and GRACE scores, identify the one of better prognostic performance in patients with STEMI.

Methods

We included 152 individuals consecutively admitted for STEMI. The TIMI and GRACE scores were tested for their discriminatory ability (C-statistics) and calibration (Hosmer-Lemeshow) in relation to hospital death.

Results

The TIMI score showed equal distribution of patients in the ranges of low, intermediate and high risk (39 %, 27 % and 34 %, respectively), as opposed to the GRACE Score that showed predominant distribution at low risk (80 %, 13 % and 7%, respectively). Case-fatality was 11%. The C-statistics of the TIMI score was 0.87 (95%CI = 0.76 to 0.98), similar to GRACE (0.87, 95%CI = 0.75 to 0.99) - p = 0.71. The TIMI score showed satisfactory calibration represented by χ2 = 1.4 (p = 0.92), well above the calibration of the GRACE score, which showed χ2 = 14 (p = 0.08). This calibration is reflected in the expected incidence ranges for low, intermediate and high risk, according to the TIMI score (0 %, 4.9 % and 25 %, respectively), differently to GRACE (2.4%, 25% and 73%), which featured middle range incidence inappropriately.

Conclusion

Although the scores show similar discriminatory capacity for hospital death, the TIMI score had better calibration than GRACE. These findings need to be validated populations of different risk profiles.