Pyrazole inhibitors of HMG-CoA reductase: an attempt to dramatically reduce synthetic complexity through minimal analog re-design

An extraordinarily potent and hepatoselective class of HMG-CoA reductase inhibitors containing a pyrazole core was recently reported; however, its development was hampered by a long and difficult synthetic route. We attempted to circumvent this obstacle by preparing closely related analogs wherein the key dihydroxyheptanoic acid sidechain was tethered to the pyrazole core via an oxygen linker ('oxypyrazoles'). This minor change reduced the total number of synthetic steps from 14 to 7. Although the resulting analogs maintained much of the in vitro and cell activity of the pyrazoles, inferior in vivo activity precluded further development. Caco-2 cell permeability data suggest that enhanced cellular efflux of the oxypyrazoles relative to the pyrazoles may be responsible for the poor in vivo activity.     

Haemosporidian Parasites of Antelopes and Other Vertebrates from Gabon,Central Africa

Re-examination, using molecular tools, of the diversity of haemosporidian parasites (among which the agents of human malaria are the best known) has generally led to rearrangements of traditional classifications. In this study, we explored the diversity of haemosporidian parasites infecting vertebrate species (particularly mammals, birds and reptiles) living in the forests of Gabon (Central Africa), by analyzing a collection of 492 bushmeat samples. We found that samples from five mammalian species (four duiker and one pangolin species), one bird and one turtle species were infected by haemosporidian parasites. In duikers (from which most of the infected specimens were obtained), we demonstrated the existence of at least two distinct parasite lineages related to Polychromophilus species (i.e., bat haemosporidian parasites) and to sauropsid Plasmodium (from birds and lizards). Molecular screening of sylvatic mosquitoes captured during a longitudinal survey revealed the presence of these haemosporidian parasite lineages also in several Anopheles species, suggesting a potential role in their transmission. Our results show that, differently from what was previously thought, several independent clades of haemosporidian parasites (family Plasmodiidae) infect mammals and are transmitted by anopheline mosquitoes.     

Novel and selective spiroindoline-based inhibitors of Sky kinase

We report the discovery of a novel series of spiroindoline-based inhibitors of Sky kinase that bind in the ATP-binding site and exhibit high levels of kinome selectivity through filling the Ala571-subpocket. These inhibitors exhibit moderate oral bioavailability in the rat due to low absorption across the gut wall.     

双源CT冠状动脉血管成像诊断心肌桥的价值探讨

目的：研究双源CT冠状动脉血管成像诊断心肌桥的临床价值。方法：选择260例具有典型心前区不适的患者进行双源CT冠脉血管成像检查,观察其发生部位,测量其长度和深度并进行分析。结果：260例受检患者中,62例共70段存在心肌桥,检出率达20.76%,高于文献报道的检出率18.2%。所有心肌桥均发生于左前降支,其中近段17段（24.4%）,中段43段（61.4%）,远段10段（14.2%）。心肌桥平均长度为15.8±6.4mm,深度为1.4±0.85mm。结论：双源CT冠状动脉血管成像因其便捷无创,不受心率严格限制且价格低廉可作为心肌桥筛查的理想检查手段。     

黑皮质素受体-4调节通路的研究进展

黑皮质素系统来自阿片-促黑素细胞皮质素原,在中枢摄食行为和能量平衡代谢中起到重要作用,此系统生理功能的发挥主要通过与下丘脑神经元细胞上特定膜受体（黑皮质素受体）结合完成。黑皮质素受体（MCR）有五种亚型（MC1R-MC5R）,其中参与体重调节的受体主要是黑皮质素受体3（MC3R）和黑皮质素受体4（MC4R）。MC4R属于G蛋白耦联受体,具有七次跨膜结构。作为一种膜受体,MC4R发挥体重调节作用,一方面受外界激动剂或拮抗剂的调节;另一方面,此受体活化后会影响到细胞内的信号调节通路。研究MC4R的功能首先要了解受体的结构,本文对G蛋白耦联受体的结构进行了较详细的叙述,MC4R经信号调节通路,激活腺苷酸环化酶,增加cAMP的浓度,最终通过影响细胞内基因的转录和翻译,来调节体重和能量的消耗。     

根施甜菜碱对镍胁迫下小麦幼苗生长生理的影响

以普通小麦品种‘轮选988’为材料,采用溶液培养法,研究了根施不同浓度甜菜碱(1.0、2.0、3.0、4.0、5.0、10.0、15.0、20.0mmol·L~(-1))对镍(100μmol·L~(-1) NiSO_4)胁迫下小麦根系生长的影响,以及4.0mmol·L~(-1)甜菜碱处理镍胁迫幼苗根系相关抗逆生理生化指标的变化。结果表明:(1)与不施加镍对照相比,镍胁迫下小麦幼苗的根长、株高、鲜重和干重分别显著降低了14.7%、11.7%、15.0%和16.7%。(2)与单独镍胁迫处理相比,小麦幼苗的根长、株高、鲜重和干重均随着根施甜菜碱的浓度逐渐增加且呈先升后降的趋势,并以4.0mmol·L~(-1)外源甜菜碱处理效果较佳。(3)与单独镍胁迫处理相比较,在4.0mmol·L~(-1)外源甜菜碱处理下,小麦幼苗根系超氧化物歧化酶(SOD)、过氧化物酶(POD)、过氧化氢酶(CAT)和抗坏血酸过氧化物酶(APX)活性分别升高了284.7%、40.3%、82.9%和20.4%,超氧阴离子自由基(O-·2)含量、过氧化氢(H_2O_2)含量和丙二醛(MDA)含量分别显著降低了50.6%、38.4%和40.6%,可溶性糖含量及游离脯氨酸(Pro)含量分别显著降低了19.2%、45.4%,而根系活力大幅上升了358.0%。研究认为,根施适宜浓度外源甜菜碱可显著增强小麦幼苗根系的抗氧化能力,恢复根系活力,从而有效减弱镍胁迫对小麦幼苗生长的伤害。     

Molecular basis of ion permeability in a voltage‐gated sodium channel

Voltage‐gated sodium channels are essential for electrical signalling across cell membranes. They exhibit strong selectivities for sodium ions over other cations, enabling the finely tuned cascade of events associated with action potentials. This paper describes the ion permeability characteristics and the crystal structure of a prokaryotic sodium channel, showing for the first time the detailed locations of sodium ions in the selectivity filter of a sodium channel. Electrostatic calculations based on the structure are consistent with the relative cation permeability ratios (Na⁺ ≈ Li⁺ ≫ K⁺, Ca²⁺, Mg²⁺) measured for these channels. In an E178D selectivity filter mutant constructed to have altered ion selectivities, the sodium ion binding site nearest the extracellular side is missing. Unlike potassium ions in potassium channels, the sodium ions in these channels appear to be hydrated and are associated with side chains of the selectivity filter residues, rather than polypeptide backbones.     

MR弥散加权成像对鉴别诊断良恶性椎体压缩性骨折的临床价值研究

目的：探讨MR弥散加权成像（DWI）鉴别诊断良恶性椎体压缩性骨折的临床价值。方法：对57例经临床或病理证实的椎体良恶性压缩性骨折患者行矢状位T1M、T2WI、T2WI／FS及DWI扫描,研究其在常规序列和DWI序列上的表现,将常规MR序列和DWI序列检出率进行比较,测量正常椎体及病变椎体的表观弥散系数（ADC）值,并进行统计学分析。结果：（1）MR常规序列和DWI序列（b=500s／mm2）表现：良性椎体压缩性骨折呈长T1长或等T2改变,T2WI／FS呈高信号,DWI可以呈高信号、等信号及低信号;恶性椎体压缩性骨折呈长T1长T2信号,大部分病灶T2WUFS及DWI呈高信号,少数变现为低信号;（2）MR常规序列和DWI序列（b=500s／mm2）病灶检出率的比较：T1WI、T2WI／FS及DWI序列病灶检出率均高于T2WI序列,其间的差别有显著性意义（P〈0．01）,T1WI、T2WI／FS及DWI序列病灶检出率之间无显著性差异（P〉0．01）;（3）ADC值比较：在DWI（b=500s／mm2）上,良性组ADC值为（2．03±0．83）×10^3mm^2/s,恶性组ADC值为（1．37±0．75）×10^-3mm^2/s,正常组ADC值为（0．36±0．21）×10^-3mm^2／s,成像条件相同时,良性组高于恶性组,两组间有明显的统计学意义（P〈0．05）。结论：DWI可较好的反映椎体的弥散特征,ADC值作为量化指标可对良恶性椎体压缩性骨折进行可靠鉴别。     

血液磁极化疗法对糖尿病兔胰岛功能的影响

目的观察血液磁极化疗法(简称血磁治疗)对糖尿病(DM)的治疗效果和对胰岛功能的影响。方法制备了四氧嘧啶DM兔模型20只,随机分为两组,即DM模型血磁治疗组及DM模型未治疗组,同时设立正常对照组10只,分别测定治疗前后空腹血糖(FPG)、糖化血红蛋白(HbA1c)、胰岛素(INS)及C-肽(C-P),并于观察期结束后处死动物取胰腺组织常规石蜡包埋切片,行HE及Mallory三色法特殊染色观察3组胰岛形态学变化。结果血磁治疗显著降低DM兔的FPG(P<0.001)。DM治疗组INS及C-P水平较治疗前明显升高(P<0.01),与未治疗组相比差异显著(P<0.05)。胰岛病理改变可见治疗组β细胞数量明显多于DM未治疗组,提示血磁疗法具有促进胰岛修复,改善胰岛功能的作用。结论血磁疗法能够促进DM时受损胰岛组织的修复,改善胰岛β细胞分泌功能,降血糖作用明显。