BACKGROUND & AIMS: :New hydrazone derivatives were synthesized via the nucleophilic addition-elimination reaction of 2-[(1-methyl-1H-tetrazol-5-yl)thio)]acetohydrazide with aromatic aldehydes/ketones. The compounds were tested in vitro against various Candida species and compared with ketoconazole. Genotoxicity of the most effective anticandidal compounds was evaluated by umuC and Ames assays. All compounds were also investigated for their cytotoxic effects on NIH3T3 and A549 cell lines. Compound 8 was the most effective antifungal derivative against C. albicans (ATCC-90028) with a MIC value of 0.05 mg/mL. Compound 5 can be identified as the most promising anticancer agent against A549 cancer cell lines due to its inhibitory effect on A549 cell lines and low toxicity to NIH3T3 cells.

背景与目标： ：通过2-[（（1-甲基-1H-四唑-5-基）硫基）]乙酰肼与芳香族醛/酮的亲核加成消除反应合成了新的衍生物。该化合物在体外针对各种念珠菌进行了测试，并与酮康唑进行了比较。通过umuC和Ames分析评估了最有效的抗候选化合物的基因毒性。还研究了所有化合物对NIH3T3和A549细胞系的细胞毒性作用。化合物8是针对白色念珠菌的最有效的抗真菌衍生物（ATCC-90028），MIC值为0.05 mg / mL。化合物5由于其对A549细胞系的抑制作用和对NIH3T3细胞的低毒性而可以被确定为最有前途的针对A549癌细胞系的抗癌剂。

BACKGROUND & AIMS: :Alkenylboronic acids have shown important biological activities that contribute to neuroprotection. We have determined their influence on the β-amyloid (βA) aggregation process, β-secretase and acethylcholinesterase activities on cell-free systems, on the redox and lipid peroxidation status, and on the vulnerability to apoptotic death in an APPswe neuroblastoma cell line, before and after hydrogen peroxide treatment. We have discovered that 2-arylvinylboronic acids and some of their esters possess a set of properties which makes them highly useful as neuroprotective agents affecting multiple biological targets involved in AD. These properties are not paralleled by the related 2-arylboronic acids.

背景与目标： 烯基硼酸已显示出重要的生物活性，可促进神经保护作用。我们已经确定了它们对β-淀粉样蛋白（βA）聚集过程，β-分泌酶和乙酰胆碱酯酶活性对无细胞系统，氧化还原和脂质过氧化状态的影响，以及对APPswe神经母细胞瘤细胞株凋亡死亡的脆弱性的影响，过氧化氢处理前后。我们已经发现2-芳基乙烯基硼酸及其某些酯具有一系列特性，这使得它们非常有用地用作影响涉及AD的多个生物学靶标的神经保护剂。这些性能是相关的2-芳基硼酸无法比拟的。

BACKGROUND & AIMS: :A series of novel resveratrol derivatives were designed, synthesised and evaluated as potential therapeutic agents for the treatment of Alzheimer's disease. Among these compounds, compound 7l, (E)-5-(4-(isopropylamino)styryl)benzene-1,3-diol, exhibited potent ß-amyloid aggregation inhibition activity, which was confirmed by a ThT fluorescence assay (71.65% at 20 μM) and transmission electron microscopy (TEM). Compound 7l also exhibited good antioxidant activity (4.12 Trolox equivalents in an oxygen radical absorbance capacity assay and a 37% reduction in reactive oxygen species in cells at 10 μM). The cytotoxicity analysis of compounds 7f, 7i, 7j and 7l indicated that these compounds have lower toxicities than resveratrol at 60 μM.

背景与目标： ：设计，合成和评估了一系列新型白藜芦醇衍生物，作为治疗阿尔茨海默氏病的潜在治疗剂。在这些化合物中，化合物7l，（E）-5-（4-（异丙基氨基）苯乙烯基）苯-1,3-二醇表现出强力的β-淀粉样蛋白聚集抑制活性，这可通过ThT荧光测定法证实（71.65％在20μM）和透射电子显微镜（TEM）。化合物7-1也表现出良好的抗氧化活性（在氧自由基吸收能力测定中为4.12 Trolox当量，并且在10μM下细胞中的活性氧减少了37％）。化合物7f，7i，7j和7l的细胞毒性分析表明，在60μM浓度下，这些化合物的毒性低于白藜芦醇。

BACKGROUND & AIMS: :In this study, we evaluated the cytotoxic activity and antiproliferative potency of novel octahydropyrazin[2,1-a:5,4-a']diisoquinoline derivatives (1-7) in MCF-7 and MDA-MB-231 breast cancer cell lines. Annexin V binding assay and disruption of the mitochondrial potential were performed to determine apoptosis. The activity of caspases 3, 8, 9, and 10 was measured after 24 h of incubation with tested compounds to explain detailed molecular mechanism of induction of apoptosis. The results from experiments were compared with effects obtained after incubation in the presence of camptothecin and etoposide. Our study demonstrated that the most active compounds in both analyzed breast cancer cell lines were compounds 3 and 4. We also observed that all compounds induced apoptosis. We demonstrated the higher activity of caspases 3, 8, 9, and 10, which confirmed that induction of apoptosis is associated with external and internal cell death pathway. Our study revealed that the novel compounds in group of diisoquinoline derivatives are promising candidates in anticancer treatment by activation of both extrinsic and intrinsic apoptotic pathways.

背景与目标： ：在这项研究中，我们评估了新型八氢吡嗪[2,1-a：5,4-a']二异喹啉衍生物（1-7）在MCF-7和MDA-MB-231乳腺癌细胞中的细胞毒活性和抗增殖能力线。进行膜联蛋白V结合测定和线粒体电位破坏以确定细胞凋亡。在与被测化合物孵育24小时后，测定了胱天蛋白酶3、8、9和10的活性，以解释诱导凋亡的详细分子机制。将实验结果与在喜树碱和依托泊苷存在下孵育后获得的效果进行比较。我们的研究表明，在两种分析过的乳腺癌细胞系中，活性最高的化合物是化合物3和4。我们还观察到所有化合物均可诱导细胞凋亡。我们证明了胱天蛋白酶3，8，9和10较高的活动，这证实凋亡的诱导与外部和内部细胞死亡途径相关。我们的研究表明，通过激活外在和内在的凋亡途径，二异喹啉衍生物类中的新化合物有望成为抗癌治疗的候选药物。

BACKGROUND & AIMS: :Antitumor agents that bind to tubulin and disrupt microtubule dynamics have attracted considerable attention in the last few years. To extend our knowledge of the thiazole ring as a suitable mimic for the cis-olefin present in combretastatin A-4, we fixed the 3,4,5-trimethoxyphenyl at the C4-position of the thiazole core. We found that the substituents at the C2- and C5-positions had a profound effect on antiproliferative activity. Comparing compounds with the same substituents at the C5-position of the thiazole ring, the moiety at the C2-position influenced antiproliferative activities, with the order of potency being NHCH(3) > Me > N(CH(3))(2). The N-methylamino substituent significantly improved antiproliferative activity on MCF-7 cells with respect to C2-amino counterparts. Increasing steric bulk at the C2-position from N-methylamino to N,N-dimethylamino caused a 1-2 log decrease in activity. The 2-N-methylamino thiazole derivatives 3b, 3d and 3e were the most active compounds as antiproliferative agents, with IC(50) values from low micromolar to single digit nanomolar, and, in addition, they are also active on multidrug-resistant cell lines over-expressing P-glycoprotein. Antiproliferative activity was probably caused by the compounds binding to the colchicines site of tubulin polymerization and disrupting microtubule dynamics. Moreover, the most active compound 3e induced apoptosis through the activation of caspase-2, -3 and -8, but 3e did not cause mitochondrial depolarization.

背景与目标： 近年来，与微管蛋白结合并破坏微管动力学的抗肿瘤剂引起了相当大的关注。为了扩展我们对噻唑环作为康美他汀A-4中顺式烯烃的合适模拟物的认识，我们将3,4,5-三甲氧基苯基固定在噻唑核心的C4位。我们发现，在C2和C5位置的取代基对抗增殖活性具有深远的影响。比较噻唑环C5位上具有相同取代基的化合物，C2位上的部分影响抗增殖活性，效力顺序为NHCH（3）> Me> N（CH（3））（2） 。相对于C 2-氨基对应物，N-甲基氨基取代基显着提高了对MCF-7细胞的抗增殖活性。从N-甲基氨基到N，N-二甲基氨基的C2位增加的空间体积导致活性降低1-2 log。 2-N-甲基氨基噻唑衍生物3b，3d和3e是最有效的化合物作为抗增殖剂，其IC（50）值从低微摩尔到一位数纳摩尔，此外，它们还对耐多药细胞具有活性系过度表达P-糖蛋白。抗增殖活性可能是由于化合物与微管蛋白聚合的秋水仙碱位点结合并破坏了微管动力学而引起的。此外，活性最高的化合物3e通过激活caspase-2，-3和-8诱导细胞凋亡，但3e不会引起线粒体去极化。

BACKGROUND & AIMS: :Phyto-psychopharmacological agents are extracts of plants with stimulating or calming effects on the central nervous system. Phyto-psycho-pharmacological agents are among the most commonly prescribed herbal medicines in Germany. The efficacy and harmlessness of some of the preparations have been established by high quality clinical trials. Between 1975 and 1992, a total of 34 clinical studies involving some 2326 patients were published on the effects of Ginkgo special extract EGb 761 and LI 1370; to date, 28 clinical trials in 2120 patients have been under-taken with alcoholic extracts of St. John's Wort. The therapeutic efficacy of kava and valerian extracts has been investigated in six and four controlled studies, respectively. In general, a high placebo effect is likely, which is why it is essential to include control groups in these studies. A considerable advantage over synthetic psychopharmacological agents is the low incidence of side effects, which in safety assessment studies is below 3%. The sharp increase in quality standards for clinical trials has meant that only a few preparations have undergone large scale testing programs in accordance with international guidelines. For other phyto-psychopharmacological agents, there is the danger that no further clinical trials will be undertaken due to the excessively high standards now demanded.

背景与目标： ：植物心理药物是对中枢神经系统具有刺激或镇定作用的植物提取物。植物心理药物是德国最常用的草药之一。某些制剂的功效和无害性已通过高质量的临床试验确定。 1975年至1992年间，共发表了34项临床研究，涉及2326例患者，研究了银杏特殊提取物EGb 761和LI 1370的作用。迄今为止，已对圣约翰草的酒精提取物进行了2120例患者的28项临床试验。卡瓦和缬草提取物的治疗功效已分别在六项和四项对照研究中进行了研究。通常，可能有很高的安慰剂作用，这就是为什么必须在这些研究中包括对照组的原因。相对于合成的心理药物而言，一个相当大的优势是副作用的发生率低，在安全性评估研究中，副作用低于3％。临床试验质量标准的急剧提高意味着，只有少数制剂按照国际准则进行了大规模的测试程序。对于其他植物心理药物，由于现在要求的标准过高，存在无法进行进一步临床试验的危险。

BACKGROUND & AIMS: :Since there are no systematic studies available on the effects of anti-microtubule agents on ciliated protozoa, we screened a wide variety of such compounds for their effects on the growth of Paramecium tetraurelia cell cultures. Compounds tested include agents of widely different chemical composition and with reported effects on widely different cell types. We can differentiate between different drug effects: (a) Rotenone is the only agent without any recognisable effect, (b) Another group of compounds (including colchicine) requires very high concentrations, as compared to higher animal cells, i.e., rather close to a cytotoxic level; this group also includes tubulozole (unexpectedly without any difference between the cis- and the trans-stereoisomer). (c) A third group of drugs inhibits cell culture growth without any lethal effects (benzimidazoles, nocodazole, parbendazole; the [anti-]fungal antibiotic, griseofulvin; the herbicide, trifluralin). (d) Finally a group of agents are active in a concentration range also reported for plants (the herbicide, APM) or for higher animal cells (including the microtubule stabiliser, taxol) or for both (vinblastine, vincristine, triethyl lead), although they are cytotoxic at higher concentrations (like compounds of group [b]). Therefore, in particular compounds of group (c) and possibly of group (d) might be considered further on for a more detailed analysis of a possibly genuine anti-microtubular effect in Paramecium cells. Of particular interest may be nocodazole, parbendazole and trifluralin, since they can inhibit cell culture growth (over 24 h tested) in relatively low concentrations (comparable to other cell types) without any impairment of cell viability.

背景与目标： ：由于尚无关于抗微管剂对纤毛虫原虫影响的系统研究，因此我们筛选了多种此类化合物对草履虫草履虫细胞培养物生长的影响。测试的化合物包括化学成分差异很大的试剂，并且据报道对多种细胞类型具有影响。我们可以区分不同的药物作用：（a）鱼藤酮是唯一没有任何可识别作用的药物，（b）与较高的动物细胞相比，另一组化合物（包括秋水仙碱）需要很高的浓度，即接近细胞毒性水平；该组还包括微管唑（出乎意料的是，顺式和反式立体异构体之间没有任何区别）。 （c）第三类药物抑制细胞培养物的生长而没有任何致死作用（苯并咪唑，诺考达唑，苯达达唑； [抗]真菌抗生素，灰黄霉素；除草剂三氟拉林）。 （d）最后，一组试剂在植物（除草剂，APM）或高级动物细胞（包括微管稳定剂，紫杉醇）或两者（长春碱，长春新碱，三乙基铅）的浓度范围内均具有活性。它们在较高浓度下具有细胞毒性（如[b]组化合物）。因此，对于草履虫细胞中可能真正的抗微管作用的更详细的分析，可以进一步考虑组（c）以及可能的组（d）的化合物。尤其值得关注的是诺考达唑，帕苯达唑和三氟拉林，因为它们可以以相对低的浓度（与其他细胞类型相比）抑制细胞培养物的生长（测试超过24小时），而不会损害细胞活力。

BACKGROUND & AIMS: :Direct-acting antiviral (DAA) agents specifically target viral proteins. Two DAAs have been already been approved for the treatment of HCV infection and many more are in development. DAA treatment of HCV infection, however, leads to the selection of viral variants (produced by the error-prone HCV polymerase) that are resistant to the DAA agent in use. The selection of DAA-resistant HCV variants has been studied extensively in vitro and in vivo. Common amino acid substitution sites in each of the non-structural proteins are associated with DAA-resistance: D168, A155, A156 and V36 in NS3 protease; L31 and Y93 in NS5A; S282, S96, P495, M423, M414 and C316 in NS5B. In this review we cover the basic principles of DAA resistance, summarise the available resistance data for the various classes of DAAs and discuss the potential of DAA combination therapy for overcoming DAA-resistance, resulting in major advances in the treatment of HCV.

背景与目标： ：直接作用抗病毒（DAA）剂专门针对病毒蛋白。已经批准了两种DAA用于治疗HCV感染，并且还有更多的药物正在开发中。但是，DAA对HCV感染的治疗导致选择对使用中的DAA剂具有抗性的病毒变体（由易出错的HCV聚合酶产生）。在体外和体内已经广泛研究了抗DAA的HCV变异体的选择。每种非结构蛋白中的常见氨基酸取代位点均与DAA耐药性相关：NS3蛋白酶中的D168，A155，A156和V36。 NS5A中的L31和Y93； NS5B中的S282，S96，P495，M423，M414和C316。在本综述中，我们涵盖了DAA耐药性的基本原理，总结了各种DAA耐药性的可用耐药性数据，并讨论了DAA联合疗法克服DAA耐药性的潜力，从而在HCV的治疗方面取得了重大进展。

BACKGROUND & AIMS: We have recently shown that the incubation of Xenopus laevis oocytes in procaine-containing solutions induced germinal vesicle breakdown without white spot formation and, in some cases, with the appearance of spindle and chromosomes in the cytoplasm. The present study was performed to determine whether M-phase promoting factor was involved in this unusual maturation. Procaine failed to induce maturation in the presence of 6-dimethylamino purine or roscovitine, which are both known to inhibit p34cdc2 kinase. Histone H1 kinase activity was detected in procaine-treated oocytes but it was always lower than in progesterone-treated controls. A shift in p34cdc2 was observed in oocytes that had been exposed to procaine for 16 h, but it was not detected in those exposed for 24 h. Finally, cytoplasm transfer experiments demonstrated that the maturation promoting activity that occurred in oocytes incubated in procaine for 16 h could induce maturation of recipient stage VI oocytes. This transferable activity was weaker than that from progesterone-treated controls since only 30% of the recipients underwent germinal vesicle breakdown and only a few spindles were observed, which were not always correctly located. Taken together these results demonstrate that M-phase promoting factor is involved in the procaine maturing effect despite some differences compared with progesterone-treated oocytes which might explain the particular type of maturation induced by this substance. The discovery of the mechanisms by which procaine is able to activate M-phase promoting factor might now help in the understanding of some steps in progesterone-induced maturation that have still to be elucidated.

背景与目标： 我们最近发现，非洲爪蟾卵母细胞在含有普鲁卡因的溶液中的孵育可诱导发芽囊泡破裂，而不会形成白点，在某些情况下，在细胞质中还会出现纺锤体和染色体。进行本研究是为了确定M期促进因子是否参与了这种异常的成熟。在6-二甲基氨基嘌呤或roscovitine的存在下，普鲁卡因无法诱导成熟，这两种物质均已知抑制p34cdc2激酶。在经普鲁卡因处理的卵母细胞中检测到组蛋白H1激酶活性，但始终低于经孕激素处理的对照组。在已暴露于普鲁卡因16 h的卵母细胞中观察到p34cdc2发生变化，但在暴露24 h的卵母细胞中未检测到。最后，细胞质转移实验表明，在普鲁卡因中孵育16 h的卵母细胞中发生的促进成熟的活性可以诱导受体VI期卵母细胞的成熟。这种可转移的活性比黄体酮治疗的对照弱，因为只有30％的接受者经历了生小泡破裂，并且仅观察到少数纺锤体，但并不总是正确定位。这些结果加在一起表明，尽管与孕酮处理的卵母细胞相比有一些差异，但M期促进因子参与了普鲁卡因的成熟作用，这可能解释了该物质诱导的特定类型的成熟。普鲁卡因能够激活M期促进因子的机制的发现，现在可能有助于了解孕激素诱导的成熟的某些步骤，这些步骤仍有待阐明。

BACKGROUND & AIMS: The effects of co-culture of human spermatozoa with human immortalized endometrial cells - epithelial or stromal - on sperm movement characteristics, including hyperactivation, were studied using computer-assisted sperm analysis (CASA). Epithelial and stromal cell types could be separated following 8-10 days of culture of endometrial cells originating from human biopsies. Both cell types were immortalized by the SV 40 large T antigen. Co-incubation of sperm with epithelial and stromal monolayers enhanced the rate of hyperactivation24.9% (P <0.05) and 17.8% (P = 0.05) versus 9.5% as control, respectively, whereas the majority of motility parameters remained unchanged. Conditioned media had no effect upon sperm parameters, including hyperactivation. Co-incubation with either monolayer was able to maintain sperm motility over a longer period than incubation in control medium alone.

In four patients whose spermatozoa did not exhibit hyperactivation, co-incubation with epithelial cells, but not conditioned medium, allowed normal rates of hyperactivation (range6.9-15.6%).

背景与目标： 使用计算机辅助精子分析（CASA）研究了人类精子与人类永生化子宫内膜细胞-上皮或基质共培养对精子运动特征（包括过度活化）的影响。在培养源自人类活组织检查的子宫内膜细胞后8-10天，可以分离上皮和基质细胞类型。两种细胞类型都可以通过SV 40大T抗原获得永生。将精子与上皮和基质单层共同孵育可提高超活化率，分别为对照组的24.9％（P <0.05）和17.8％（P = 0.05），而对照组为9.5％，而大多数运动参数保持不变。条件培养基对精子参数没有影响，包括过度激活。与单独在对照培养基中孵育相比，与任一单层一起共同孵育能够在更长的时间内维持精子活力。

在四名精子未表现出过度激活的患者中，与上皮细胞共同孵育，但不与条件培养基共同孵育，允许正常的过度激活率（范围6.9-15.6％）。

BACKGROUND & AIMS: :In the developing mammalian central nervous system astrocytes have been proposed as an important substrate for axon growth. In the adult central nervous system following injury, astrocytes are a major component of the gliotic response which has been proposed to block axon growth. Experimental transplantation studies using cultured astrocytes have suggested that immature but not mature cultured astrocytes have the capacity to support axon outgrowth when transplanted into the adult rodent CNS. These observations suggest that astrocyte maturation is accompanied by changes in the functional capacity of these cells to support axon outgrowth. To determine whether this functional change reflects an intrisic astrocyte property, the extent and molecular bases of neurite outgrowth from embryonic rat cortical and chick retinal neurons on cultures of purified immature and mature astrocytes have been compared in vitro. The rate and extent of neurite outgrowth from both neuronal populations are consistently greater over the surface of immature than over the surface of mature astrocytes. Furthermore, antibodies to NCAM and G4/L1 significantly reduce neurite outgrowth on immature but not mature astrocytes, while antibodies to the integrin B1 receptor reduced outgrowth on both immature and, to a lesser extent, mature astrocytes. These results suggest that in vitro mature astrocytes have a reduced capacity and different molecular bases for supporting neurite outgrowth compared to immature astrocytes and are consistent with the proposal that functional changes during astrocyte maturation may partially contribute to regulating axon growth in the mammalian CNS.

背景与目标： ：在发展中的哺乳动物中枢神经系统中，星形胶质细胞已被提议作为轴突生长的重要底物。在损伤后的成年中枢神经系统中，星形胶质细胞是神经胶质反应的主要成分，已被提议阻断轴突的生长。使用培养的星形胶质细胞进行的实验性移植研究表明，当移植到成年啮齿动物中枢神经系统中时，未成熟但不是成熟的培养星形胶质细胞具有支持轴突生长的能力。这些观察结果表明，星形胶质细胞的成熟伴随着这些细胞支持轴突生长的功能能力的变化。为了确定这种功能变化是否反映了内在的星形胶质细胞特性，在体外比较了纯化的未成熟和成熟的星形胶质细胞培养物中胚胎大鼠皮层和鸡视网膜神经元神经突生长的程度和分子基础。来自两个神经元群体的神经突向外生长的速率和程度在未成熟的表面上始终比在成熟的星形胶质细胞表面上大。此外，针对NCAM和G4 / L1的抗体可显着减少未成熟但未成熟的星形胶质细胞上的神经突生长，而针对整联蛋白B1受体的抗体则可减少未成熟的星形胶质细胞（在较小程度上）减少的星形胶质细胞的生长。这些结果表明，与不成熟的星形胶质细胞相比，体外成熟的星形胶质细胞具有降低的能力和支持神经突生长的不同分子基础，并且与在星形胶质细胞成熟过程中功能改变可能部分有助于调节哺乳动物中枢神经系统中轴突生长的提议相一致。

BACKGROUND & AIMS: The potency of conventional inhaled anesthetics increases with maturationthe 50% effective dose (minimum alveolar anesthetic concentration [MAC]) for conventional inhaled anesthetics in the neonatal rat or human exceeds MAC in the young adult. This increase also applies to ethanol in rats tested using MAC as the measure of anesthesia. However, the converse appears to be true for studies in mice assessed with the righting reflex; that is, adult mice are six times more resistant than neonates to the effects of ethanol. These disparate findings imply that maturation in rats and mice may produce opposing changes in the quantity or sensitivity of one or more receptors that mediate the actions of anesthetics that lead to the anesthetic state. Such a finding would be important for two reasons. First, both rodents are widely used in studies of anesthetic effects, and, thus, a species-dependent divergence in anesthetic effects has immediate experimental implications. Second, confirmation of such a species difference would supply an opportunity to test which receptors might be crucial to anesthetic mechanisms. Accordingly, we investigated whether maturation decreased ethanol potency in mice, using MAC as the measure of anesthesia. Applying standard techniques, we tested MAC for ethanol in 15 CF-1 mice aged 10 days (6-8.5 g) and in 13 mice aged 77-84 days (34-39 g). MAC decreased with maturation, and the decrease was indistinguishable from that found in our previous studies of rats.

背景与目标： 常规吸入麻醉剂的效力随着成熟而增加，新生大鼠或人中常规吸入麻醉剂的50％有效剂量（最小肺泡麻醉剂浓度[MAC]）超过了年轻成年人的MAC。这种增加也适用于使用MAC作为麻醉手段测试的大鼠中的乙醇。但是，对于用扶正反射评估的小鼠研究似乎相反。也就是说，成年小鼠对乙醇的抵抗力是新生小鼠的六倍。这些不同的发现暗示，大鼠和小鼠的成熟可能在介导导致麻醉状态的麻醉剂作用的一种或多种受体的数量或敏感性方面产生相反的变化。这样的发现很重要，原因有两个。首先，两种啮齿动物都广泛用于麻醉作用的研究，因此，麻醉作用中物种依赖性的差异具有直接的实验意义。其次，确认这种物种差异将提供一个机会来测试哪些受体可能对麻醉机制至关重要。因此，我们使用MAC作为麻醉手段，研究了成熟是否降低了小鼠的乙醇效力。应用标准技术，我们在10天（6-8.5 g）的15只CF-1小鼠和77-84天（34-39 g）的13只小鼠中测试了MAC的乙醇含量。 MAC随着成熟而降低，并且与我们先前的大鼠研究没有明显的区别。

BACKGROUND & AIMS: :Many studies have shown how a 'paternal effect' can cause repeated assisted reproduction failures. In particular, with increasing experience of intracytoplasmic sperm injection (ICSI), it became evident that spermatozoa from some patients repeatedly fail to form viable embryos, although they can fertilize the oocyte and trigger early preimplantation development. Many authors have shown how this paternal effect can be traced back to anomalies in sperm chromatin organization: the spermatozoa of subfertile men are characterized by numerical abnormalities in spermatozoal chromosome content, Y chromosome microdeletions, alterations in the epigenetic regulation of paternal genome and non-specific DNA strand breaks. In particular, pathologically increased sperm DNA fragmentation is one of the main paternal-derived causes of repeated assisted reproduction failures in the ICSI era. The intention of this review is to describe nuclear sperm DNA damage, with emphasis on its clinical significance and its relationship with male infertility. Assessment of sperm DNA damage appears to be a potential tool for evaluating semen samples prior to their use in assisted reproduction, helping to select spermatozoa with intact DNA or with the least amount of DNA damage for use in assisted conception.

背景与目标： ：许多研究表明，“父亲效应”会如何导致反复的辅助生殖衰竭。特别地，随着胞浆内精子注射（ICSI）经验的增加，很明显，一些患者的精子反复无法形成有生命的胚胎，尽管它们可以使卵母细胞受精并触发早期植入前的发育。许多作者已经证明了这种父本效应如何可以追溯到精子染色质组织的异常：不育男性的精子的特征是精子体染色体含量，Y染色体微缺失，父系基因组的表观遗传调控的改变和非特异性的数值异常。 DNA链断裂。特别是，病理上增加的精子DNA片段化是ICSI时代反复辅助繁殖失败的父系原因之一。这篇综述的目的是描述核精子DNA损伤，重点是其临床意义及其与男性不育的关系。精子DNA损伤的评估似乎是评估精液样本用于辅助生殖之前的潜在工具，有助于选择具有完整DNA或DNA损伤最少的精子用于辅助受孕。

BACKGROUND & AIMS: :When females mate promiscuously, sperm from rival males compete within the female reproductive tract to fertilize ova. Sperm competition is a powerful selective force that has shaped sexual behavior, sperm production, and sperm morphology. However, nothing is known about the influence of sperm competition on fertilization-related processes, because it has been assumed that sperm competition only involves a race to reach the site of fertilization. We compared four closely related rodent species with different levels of sperm competition to examine whether there are differences in the proportion of spermatozoa that become ready to interact with the ovum ("capacitated") and in the proportion of spermatozoa that experience the acrosome reaction in response to a natural stimulant. Our results show that differences between species in levels of sperm competition were associated with the proportion of spermatozoa that undergo capacitation and with the proportion of spermatozoa that respond to progesterone, an ovum-associated signal. Sperm competition thus favors a larger population of spermatozoa that are competent to fertilize, and spermatozoa that are more sensitive to the signals emitted by the ovum and that may penetrate the ova vestments more rapidly. These results suggest that, contrary to previous assumptions, competition between spermatozoa from rival males continues at the site of fertilization. These findings may have further evolutionary implications because the enhanced competitiveness of spermatozoa during fertilization may increase the risk of polyspermy to females. This could lead to antagonistic coevolution between the sexes and may contribute to the explanation of the rapid divergence observed in fertilization-related traits.

背景与目标： ：当雌性交配时，雄性对雄的精子在雌性生殖道内竞争，使卵子受精。精子竞争是一种强大的选择性力量，已经改变了性行为，精子产生和精子形态。但是，关于精子竞争对与受精有关的过程的影响一无所知，因为人们认为精子竞争仅涉及到到达受精位的竞赛。我们比较了具有不同精子竞争水平的四种密切相关的啮齿动物，以检查准备与卵子相互作用的精子的比例（“有能力的”）和经历顶体反应的精子的比例是否存在差异。天然的兴奋剂。我们的结果表明，不同物种之间精子竞争水平的差异与经历了获能的精子的比例以及对孕激素（与卵子相关的信号）作出反应的精子的比例有关。因此，精子竞争有利于有更多的受精能力的精子，而精子对卵子发出的信号更敏感并且可以更快地穿透卵巢。这些结果表明，与以前的假设相反，来自受敌雄性的精子之间的竞争在受精地点继续进行。这些发现可能具有进一步的进化意义，因为受精过程中精子竞争能力的增强可能会增加女性多精子的风险。这可能会导致两性之间的对抗性协同进化，并可能有助于解释受精相关性状中观察到的快速分歧。

BACKGROUND & AIMS: :The study of the ultrastructure of spematozoa by means of transmission electron microscopy often presents with problems of interpretation according to the method employed, depending on whether samples are either centrifuged previously to the fixation or immersed in viscous gels. The major problems of interpretation are: changes in the location of vesicles originated during the maturation process and modifications in the adsorption of seminal plasma proteins to the sperm membrane surface. The aim of our study is to communicate an original new method for the treatment of spermatozoa for ultrastructural study. Our method is based on the use of animal tissues as biological containers, inside which the spermatic suspensions are included. We developed this method using fresh sperm samples taken from mature Rasa aragonesa rams. As biological container, we used 2.5-cm long segments of the intestine of 1-week-old chickens (Gallus gallus) (diameter around 4 mm). To avoid any influence of digestive enzymes of the mucosa on the sperm surface, we put each intestine fragment inside out by means of microdissection forceps under bifocal optical microscope and cold light. One of the edges was tied with thin suture silk. The sperm suspension was injected in the optimal experimental condition and amount. Finally, the still open edge of the intestine segment was tied with silk in the same way as the other segment edge. By using this technique, we can perform a suitable morphological study at an ultrastructural level. In addition, the functional relationship of the ultrastructural components of the target cells is correctly preserved.

背景与目标： ：根据透射电子显微镜对血吸虫超微结构的研究通常会遇到根据所用方法进行解释的问题，这取决于样品是预先离心至固定液还是浸入粘性凝胶中。解释的主要问题是：在成熟过程中产生的囊泡位置的变化以及精浆蛋白对精子膜表面的吸附作用的改变。我们研究的目的是为了交流用于超微结构研究的治疗精子的原始新方法。我们的方法是基于将动物组织用作生物容器，其中包含了精子悬浮液。我们使用从成熟的Rasa aragonesa公羊中提取的新鲜精子样本开发了这种方法。作为生物容器，我们使用了2.5周长的1周龄鸡（鸡胆）的肠段（直径约4毫米）。为了避免粘膜消化酶对精子表面的任何影响，我们在双焦点光学显微镜和冷光下通过显微解剖钳将每个肠段内翻。边缘之一用细缝线缝合。以最佳实验条件和最佳剂量注射精子悬浮液。最后，肠段的仍然开放的边缘与另一段边缘的相同方式用丝绸绑在一起。通过使用这种技术，我们可以在超微结构水平上进行合适的形态学研究。另外，正确保留了靶细胞超微结构成分的功能关系。