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1.
Squalene synthase (SS) catalyzes the biosynthesis of squalene, the first specific intermediate in the cholesterol biosynthetic pathway. To test the feasibility of lowering plasma cholesterol by inhibiting hepatic SS, we generated mice in which SS is specifically knocked out in the liver (L-SSKO) using Cre-loxP technology. Hepatic SS activity of L-SSKO mice was reduced by >90%. In addition, cholesterol biosynthesis in the liver slices was almost eliminated. Although the hepatic squalene contents were markedly reduced in L-SSKO mice, the hepatic contents of cholesterol and its precursors distal to squalene were indistinguishable from those of control mice, indicating the presence of sufficient centripetal flow of cholesterol and/or its precursors from the extrahepatic tissues. L-SSKO mice showed a transient liver dysfunction with moderate hepatomegaly presumably secondary to increased farnesol production. In a fed state, the plasma total cholesterol and triglyceride were significantly reduced in L-SSKO mice, primarily owing to reduced hepatic VLDL secretion. In a fasted state, the hypolipidemic effect was lost. mRNA expression of liver X receptor α target genes was reduced, while that of sterol-regulatory element binding protein 2 target genes was increased. In conclusion, liver-specific ablation of SS inhibits hepatic cholesterol biosynthesis and induces hypolipidemia without increasing significant mortality.  相似文献   
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Herbivory is a fundamental process that controls primary producer abundance and regulates energy and nutrient flows to higher trophic levels. Despite the recent proliferation of small‐scale studies on herbivore effects on aquatic plants, there remains limited understanding of the factors that control consumer regulation of vascular plants in aquatic ecosystems. Our current knowledge of the regulation of primary producers has hindered efforts to understand the structure and functioning of aquatic ecosystems, and to manage such ecosystems effectively. We conducted a global meta‐analysis of the outcomes of plant–herbivore interactions using a data set comprised of 326 values from 163 studies, in order to test two mechanistic hypotheses: first, that greater negative changes in plant abundance would be associated with higher herbivore biomass densities; second, that the magnitude of changes in plant abundance would vary with herbivore taxonomic identity. We found evidence that plant abundance declined with increased herbivore density, with plants eliminated at high densities. Significant between‐taxa differences in impact were detected, with insects associated with smaller reductions in plant abundance than all other taxa. Similarly, birds caused smaller reductions in plant abundance than echinoderms, fish, or molluscs. Furthermore, larger reductions in plant abundance were detected for fish relative to crustaceans. We found a positive relationship between herbivore species richness and change in plant abundance, with the strongest reductions in plant abundance reported for low herbivore species richness, suggesting that greater herbivore diversity may protect against large reductions in plant abundance. Finally, we found that herbivore–plant nativeness was a key factor affecting the magnitude of herbivore impacts on plant abundance across a wide range of species assemblages. Assemblages comprised of invasive herbivores and native plant assemblages were associated with greater reductions in plant abundance compared with invasive herbivores and invasive plants, native herbivores and invasive plants, native herbivores and mixed‐nativeness plants, and native herbivores and native plants. By contrast, assemblages comprised of native herbivores and invasive plants were associated with lower reductions in plant abundance compared with both mixed‐nativeness herbivores and native plants, and native herbivores and native plants. However, the effects of herbivore–plant nativeness on changes in plant abundance were reduced at high herbivore densities. Our mean reductions in aquatic plant abundance are greater than those reported in the literature for terrestrial plants, but lower than aquatic algae. Our findings highlight the need for a substantial shift in how biologists incorporate plant–herbivore interactions into theories of aquatic ecosystem structure and functioning. Currently, the failure to incorporate top‐down effects continues to hinder our capacity to understand and manage the ecological dynamics of habitats that contain aquatic plants.  相似文献   
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CLN025 is one of the smallest fast-folding proteins. Until now it has not been reported that CLN025 can autonomously fold to its native conformation in a classical, all-atom, and isothermal–isobaric molecular dynamics (MD) simulation. This article reports the autonomous and repeated folding of CLN025 from a fully extended backbone conformation to its native conformation in explicit solvent in multiple 500-ns MD simulations at 277 K and 1 atm with the first folding event occurring as early as 66.1 ns. These simulations were accomplished by using AMBER forcefield derivatives with atomic masses reduced by 10-fold on Apple Mac Pros. By contrast, no folding event was observed when the simulations were repeated using the original AMBER forcefields of FF12SB and FF14SB. The results demonstrate that low-mass MD simulation is a simple and generic technique to enhance configurational sampling. This technique may propel autonomous folding of a wide range of miniature proteins in classical, all-atom, and isothermal–isobaric MD simulations performed on commodity computers—an important step forward in quantitative biology.  相似文献   
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Unique species of ceramide (Cer) with very-long-chain polyunsaturated fatty acid (VLCPUFA), mainly 28–32 carbon atoms, 4–5 double bonds, in nonhydroxy and 2-hydroxy forms (n-V Cer and h-V Cer, respectively), are generated in rat spermatozoa from the corresponding sphingomyelins during the acrosomal reaction. The aim of this study was to determine the properties of these sperm-distinctive ceramides in Langmuir monolayers. Individual Cer species were isolated by HPLC and subjected to analysis of surface pressure, surface potential, and Brewster angle microscopy (BAM) as a function of molecular packing. In comparison with known species of Cer, n-V Cer and h-V Cer species showed much larger mean molecular areas and increased molecular dipole moments in liquid expanded phases, which suggest bending and partial hydration of the double bonded portion of the VLCPUFA. The presence of the 2-hydoxyl group induced a closer molecular packing in h-V Cer than in their chain-matched n-V Cer. In addition, all these Cer species showed liquid-expanded to liquid-condensed transitions at room temperature. Existence of domain segregation was confirmed by BAM. Additionally, thermodynamic analysis suggests a phase transition close to the physiological temperature for VLCPUFA-Cers if organized as bulk dispersions.  相似文献   
6.
We recently published two papers detailing the structures of fluid phase phosphatidylglycerol (PG) lipid bilayers (Ku?erka et al., 2012 J. Phys. Chem. B 116: 232–239; Pan et al., 2012 Biochim. Biophys. Acta Biomembr. 1818: 2135–2148), which were determined using the scattering density profile model. This hybrid experimental/computational technique utilizes molecular dynamics simulations to parse a lipid bilayer into components whose volume probabilities follow simple analytical functional forms. Given the appropriate scattering densities, these volume probabilities are then translated into neutron scattering length density (NSLD) and electron density (ED) profiles, which are used to jointly refine experimentally obtained small angle neutron and X-ray scattering data. However, accurate NSLD and ED profiles can only be obtained if the bilayer's chemical composition is known. Specifically, in the case of neutron scattering, the lipid's exchangeable hydrogens with aqueous D2O must be accounted for, as they can have a measureable effect on the resultant lipid bilayer structures. This was not done in our above-mentioned papers. Here we report on the molecular structures of PG lipid bilayers by appropriately taking into account the exchangeable hydrogens. Analysis indicates that the temperature-averaged PG lipid areas decrease by 1.5 to 3.8 Å2, depending on the lipid's acyl chain length and unsaturation, compared to PG areas when hydrogen exchange was not taken into account.  相似文献   
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目的:研究甲亢低骨量患者131I治疗后干预治疗的效果。方法:对100例甲亢低骨量患者,随机分为两组:A组50例,131I治疗后口服钙尔奇D及罗盖全治疗;B组50例,131I治疗后骨质自然恢复。另设C组50例为正常对照组。于131I治疗前、治疗后3、6及12个月测定A、B两组骨密度(BMD),观察其骨质变化并评价治疗效果。结果:(1)A组随治疗时间延长BMD逐渐升高,具有一定的规律性,腰椎(L2-4)骨密度3个月提高明显(t=-2.111,P=0.04)且12个月时达到与C组无统计学差异(t=-2.290,P=0.202)。(2)B组3个月时腰椎BMD有所降低,12个月时升高明显(股骨颈t=-2.327,P=0.043;腰椎(L2-4)t=-2.798,P=0.000)。(3)6个月时两组腰椎骨密度改善幅度出现统计学差异(t=-2.416,P=0.018),12个月时差异显著(t=-3.259,P=0.002)。结论:131I联合钙尔奇D与罗盖全治疗甲亢低骨量患者,其恢复时间及疗效均用131I治疗,能有效防止骨量的进一步下降及减少骨质疏松症的发生。  相似文献   
8.
目的:研究去甲基化药物5-氮杂胞嘧啶核苷(5-Azacytidine,5-Aza-C)对鼻咽癌细胞端粒长度及细胞生长增殖的影响。方法: 常规培养鼻咽癌CNE,CNE1,CNE2 及5-8F细胞系,5-Aza-C 处理鼻咽癌细胞后,甲基化测序聚合酶链反应(MSP)法检测亚端粒 区D4Z4 甲基化,端粒限制性片断检测端粒长度,CCK-8 检测细胞增殖。结果:2.5 uM浓度的5-Aza-C处理后,亚端粒区D4Z4 序 列的甲基化水平明显下降,约在15-20%之间,与处理前的甲基化水平(35-48%)有明显差异,差异均有统计学意义(P < 0.05)。在1 uM和2.5 uM浓度的5-Aza-C 处理后,四种细胞的端粒长度明显缩短,长度在2-4.5kb 之间,差异具有统计学意义(P < 0.05)。5uM 的5-Aza-C处理72 h 后,CNE,CNE1,CNE2 和5-8F 的生存率分别为51.27%,50.46%,48.85%,48.83%,10 uM 的5-azaC 处理72 h 后,CNE,CNE1,CNE2 和5-8F的生存率分别为31.64%,32.34%,30.01%,32.10%,与对照组比较差异有统计学意义(P<0.01)。结 论:5-Aza-C 能缩短端粒长度,抑制鼻咽癌细胞生长增殖活性。  相似文献   
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Osteoporosis is one of the most prevalent skeletal disorders and has enormous public health consequences due to the morbidity and mortality of the resulting fractures. This article discusses the developmental origins of osteoporosis and outlines some of the modifiable and non-modifiable risk factors in both intrauterine and postnatal life that contribute to the later onset of osteoporosis. Evidence for the effects of birth size and early growth in both preterm and term born infants are discussed and the role of epigenetics within the programming hypothesis is highlighted. This review provides compelling evidence for the developmental origins of osteoporosis and highlights the importance of osteoporosis prevention at all stages of the life course.  相似文献   
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