Use of large-scale chromatography in the preparation of armodafinil

Armodafinil, the (R)-enantiomer of modafinil, is a medication used to treat the excessive sleepiness associated with narcolepsy, obstructive sleep apnea/hypopnea syndrome, and shift work sleep disorder. We report here the chemical development of armodafinil and the investigations that led to a commercial route to prepare this pure enantiomer. Three synthetic approaches were used to provide the chiral sulfoxide. Resolution via preferential crystallization was used for phase I clinical trials and was subsequently replaced by chiral chromatography, enabling us to pursue a rapid filing and registration of the API. Finally, the commercial route was developed and employed asymmetric oxidation catalyzed by a titanium(IV) isopropoxide and diethyl tartrate system. The advantages of choosing a chromatographic development pathway to expedite registration while concurrently developing an economical chiral synthesis route is discussed in the context of armodafinil development.     

胚珠发育的分子机理

胚珠是研究器官形态发生和模式建成遗传分子机理的一个理想系统。近年来, 关于胚珠特征的决定、模式建成、珠被形态建成和胚囊形成等发育事件分子机理的研究取得了重要进展, 初步建立了胚珠发育的基因调控模型。同时, 离体花器官再生系统为研究激素调控胚珠发育的机理提供了有效途径。本文对拟南芥(Arabidopsis thaliana)胚珠发育的分子调控机制进行了综述。     

Starting Points for a Developmental Genetics of Nerve Patterns

SYNOPSIS. The genie control of the development of neural morphologyand specific neural connections is little known, primarily becauseof a paucity of neurological mutants in animal models suitablefor experimental manipulation. However, by using cell markers—suchas tetraploidy, a large cell marker whose development is describedhere—the development of single retinal cells in tetraploidembryos, the growth of marked polyclones in chimeric eyes, andthe central connections of various chimeric eyes have been analyzedto identify the strategies used in molding eye morphology andestablishing precise central connections. Theoretical modelsand computer simulations were used to draw inferences aboutthe information used to accomplish the identified strategies.This analysis resulted in predictions about the sorts of mutantgenes which might be found to affect neural ontogeny.     

Fishery-induced changes in a marine ecosystem: insight from models of the Gulf of Thailand

Two mass-balance trophic models are constructed to describe the Gulf of Thailand ecosystem (10–50 m depth): one model pertains to the initial phase of fisheries development, and the other to when the resources were severely depleted. The two phases are compared, and changes brought about by fishing discussed. A dynamic simulation model, Ecosim, is then used successfully to reproduce the 1980 state of the fishery based on the 1963 model and the development in catches. In addition the 1980 model is used to predict how the ecosystem groups may bounce back following marked reduction in fishing pressure. Finally, the 1963 model is used to study alternative scenarios for how the fisheries development could take place, notably the effect of exploiting only the resources of larger species. The study validates that the Ecosim model can be used to predict ecosystem level changes following changes in fishing pressure, therefore fishing induced changes can to a large extent explain the changes in ecosystem pools and fluxes observed over time.     

林业资源型城市生态-经济-社会协调发展的定量测度——以黑龙江省伊春市为例

把握城市独特的生态-经济-社会系统协调优化特性是实现林业资源型城市可持续发展的重要前提。研究从生态、经济、社会3个维度构建了林业资源型城市复合系统的测度评价指标体系,应用熵值法、耦合协调度模型,采用2005-2018年时段生态、经济、社会数据,对伊春协调发展状况进行实证测度评价,运用障碍度模型分析影响系统协调发展的主要因素,采用GM （1,1）灰色预测模型进行发展预测。结果表明：（1）综合发展指数呈上升态势,促进生态-经济-社会综合发展的主要动能历经了从生态到经济,再到生态为主要动力的发展过程,三个子系统发展水平呈趋同态势,推动三维系统的均衡协同是未来发展的重要方向;（2）三维系统耦合度稳定在较高水平,系统间相互依赖、相互作用程度较高,协调度呈波动上升,实现了由勉强协调、经济滞后发展向良好协调、同步发展的转变,协调状态趋向良好;（3）三维系统中社会子系统对协调发展的障碍度最大;人口自然增长率、建成区绿化覆盖率、GDP增长率、第三产业就业人数比重4个指标是制约近期协调发展的主要障碍因子;（4）2019-2030年,生态、经济、社会子系统发展指数及协调度的预测值均呈上升态势,生态-经济-社会复合系统将向更高级的协调发展状态演进,经济发展将再次成为促进生态-经济-社会综合发展的主要动力;加强生态建设,引领生态创新,大力发展生态经济,提高社会发展水平,着力降低障碍因子对协调发展的阻力作用,实现生态-经济-社会的联动健康发展是伊春未来重要的努力方向。     

Inhibition of follicular development induced by chronic unpredictable stress is associated with growth and differentiation factor 9 and gonadotropin in mice

Chronic psychosocial stress negatively affects ovarian function. Ovarian follicular development is regulated by both pituitary-derived gonadotropins and intraovarian regulatory factors. To date, the suppressive effects of chronic stress on the ovary have been observed to be manifested mainly as an inhibition of gonadotropin release. It is not clear whether there are any other intraovarian regulatory mechanisms involved in this process. Growth and differentiation factor 9 (GDF9) is an important, oocyte-specific paracrine regulator required for follicular development. In this study, the chronic unpredictable mild stress model was used to produce psychosocial stress in mice. The number of different developmental stages of follicles was counted on ovarian sections stained with hematoxylin and eosin. Real-time PCR and Western blotting were used to detect the mRNA and protein levels, respectively, of GDF9. The results show that chronic unpredictable stress inhibits follicular development, increases follicular atresia, and suppresses GDF9 expression. Exogenous gonadotropin treatment partly restores the repressed antral follicular development, but has no effect on the repressed secondary follicular development associated with chronic stress. Treatment with recombinant GDF9 restores secondary follicular development. Cotreatments with GDF9 and gonadotropins restore both secondary and antral follicular development in stressed mice. These findings demonstrate that inhibition of follicular development induced by chronic unpredictable stress is associated with GDF9 and gonadotropin.     

A molecular marker confirms that the rate of adult maturation is largely independent of the rate of pre-adult development in Drosophila melanogaster

The separation of adult from pre-adult life seen with animals such as Drosophila melanogaster, which are holometabolous and undergo complete metamorphosis, provides the opportunity to examine the contribution of pre-adult rate of development on the rate of maturation and aging of the adult. Recent work has shown that when ambient temperature is used to alter the rate of development there is little effect on adult life span. From this work it has been concluded that the rate of aging is largely independent of the rate of pre-adult development. However, the techniques used to examine life span did not allow for the examination of the earliest events of adult life. Our experimental design used a molecular marker linked to life span as a sensitive measure of determining physiological age. In this way, we were able to evaluate the effect of pre-adult rate of development on the earliest events of adult life. Using ambient temperature to alter both the rate of development in the pre-adult and the rate of aging in the adult independently, we were able to show that it is the ambient temperature at which the adults are living that is the principle determinant of the rate of maturation and aging of the adult. Little effect was seen on the rate of adult maturation in response to an acceleration or a slowing down of the rate of pre-adult development as measured by our molecular marker. These data support the conclusions drawn by others who examined the effect of the rate of development on adult life expectancy. The timing mechanisms at work during pre-adult and adult life appear to be largely regulated separately. If there is such a thing as a physiological clock, it appears to be reset upon eclosion. © 1996 Wiley-Liss, Inc.     

马铃薯生育期和干物质积累的动态模拟研究

根据三年的田间试验数据和有关气象资料,提出了马铃薯生育期和干物质积累的模拟模型、用高斯方程计算每天的温度条件对马铃薯生育期和干物质积累的生理效应,改进了前人的生育期模型和温度条件对干物质积累影响系数的计算方法．以每天的单位叶面积变化、群体上方的有效辐射和温度变化模拟群体的干物质积累、结果表明,本研究的模型有明确的机理性和较高的精度．用Visual Basic 6．0界面表达每日生态条件变化对群体光合生产和干物质积累的影响,模拟结果具有直观的机理性,从而克服了同类研究中的缺陷。     

Intraspecific variation of thermal reaction norms for development in insects: New approaches and prospects

The main parameters (thermal constants) characterizing the effects of constant temperatures on the duration and rate of development in ectotherms are considered. The advantages and drawbacks of the linear and nonlinear models describing the dependence of the development rate on temperature are discussed. The main patterns of interspecific variation of thermal constants in insects are described. The development of new ideas in the study of intraspecific variation of thermal reaction norms for development in insects is examined. The discrepancies in the data and their interpretation in this field are shown to result mostly from using the traditional methods of determining thermal constants. According to this method, the development rates calculated as reciprocals of the mean development times at each experimental temperature are used for regression analysis. The standard errors calculated according to this method are usually too large. Instead, a fundamentally new method is employed by the authors, according to which the individual development rates calculated for each individual are used for regression analysis of the reciprocals of the mean development times. This method reduces the standard errors of thermal constants by about an order and reveals significant differences between populations and other groups of insects. New data on intraspecific variation of the thermal reaction norms for development in Myrmica ants, the linden bug Pyrrhocoris apterus, and Calliphora blowflies are briefly described and discussed. The possible adaptive significance of these forms of intraspecific variation is discussed. The prospects of research in this new field are outlined.     

胚珠发育的分子机理

胚珠是研究器官形态发生和模式建成遗传分子机理的一个理想系统.近年来,关于胚珠特征的决定、模式建成、珠被形态建成和胚囊形成等发育事件分子机理的研究取得了重要进展,初步建立了胚珠发育的基因调控模型.同时,离体花器官再生系统为研究激素调控胚珠发育的机理提供了有效途径.本文对拟南芥(Arabidopsis thaliana)胚珠发育的分子调控机制进行了综述.     

Age determination in the Red fox (Vulpes vulpes)–an evaluation of technique efficiency as applied to a sample of suburban foxes

A review of age determination techniques that have been applied to the family Canidae is presented. It is shown that the pattern of growth and development of the various species is very similar, the rate of development being greater in the smaller, shorter-lived species, and vice versa.
The occurrence of annuli in the hard tissues of London foxes is demonstrated; these annuli can be used reliably for age determination, despite suggestions that temperate zone animals from weakly continental climates have indistinct annuli. The objective ages determined by cementum annuli are then used to investigate the value of less time-consuming age determination techniques, particularly in the separation of the young-of-the-year from adults. The results obtained from different studies vary, and these differences are discussed. It is suggested that the speed of development varies slightly in different Red fox populations, and so caution must be exercised before data from one population areapplied to another population.     

Competitive ability of neotropical Drosophila predicted from larval development times

Interspecific competition is a major aspect of the ecology of insect communities exploiting ephemeral and fragmented resources. To generate testable predictions on the role of competition in such communities, information is required about the competitive abilities of the species involved. In this study we test whether larval development time, an important life-history trait, can be used to predict interspecific competitive ability in neotropical Drosophila species. Based on earlier work, we predicted a negative relationship between larval development time and competitive ability. Pairwise competition experiments were conducted with seven Drosophila species (in all possible combinations) that are known to coexist in central Panama and represent a wide range of larval development times. We used a novel approach to determine experimental densities, standardising total larval food requirements, and thereby increasing the resolution for detecting general traits involved in exploitation competition. The effects of competition were measured by comparing values for three fitness-related parameters (thorax length, larval survival, and total mass of emerged adults) against their values at two levels of intraspecific competition. The outcomes of the pairwise competition were significantly explained by the differences in larval development times: within species pairs, species with a longer development suffered more from interspecific competition than those with shorter development. It is argued that larval development time is a major determinant of competitive rank order among drosophilid species, allowing testable community-wide predictions. In addition, this relationship provides a basis for studying the role of life-history trade-offs in community-level processes. Given the generality of the Drosophila biology, development time is expected to play a similar role in other insect communities exploiting ephemeral and fragmented resources.     

Isolation and characterization of perithecial development mutants in neurospora

The isolation and characterization of mutants that block perithecial development in Neurospora crassa are described. Several classes of mutants have been isolated after UV mutagenesis, and those that block perithecial development when used as the female (protoperithecial) component of a cross have been further characterized. These mutants fall into 29 complementation groups. Twelve of the 33 mutants block development at the protoperithecial stage; no other clustering of block points is observed. Many of the mutants show an altered vegetative growth rate as well; in several mutants this lower growth rate cosegregates with the female sterile phenotype. Only one mutant also blocks development of the perithecium when used as the conidial parent. None of the mutants are temperature sensitive; two can be suppressed by growth on a complete crossing medium. There is no indication that the mutants are at or in the mating-type locus, nor are any of the mutants mating-type specific. Genetic mosaics have been formed using mixtures of mutant and marked wild-type nuclei; no mutants are cell autonomous by this criterion. The significance of these results in terms of "developmental" mutants isolated in other organisms and in relation to models of eukaryotic development is discussed.     

Application of QbD Principles for the Evaluation of Empty Hard Capsules as an Input Parameter in Formulation Development and Manufacturing

Understanding the product and process variable on the final product performance is an essential part of the quality-by-design (QbD) principles in pharmaceutical development. The hard capsule is an established pharmaceutical dosage form used worldwide in development and manufacturing. The empty hard capsules are supplied as an excipient that is filled by pharmaceutical manufacturers with a variety of different formulations and products. To understand the potential variations of the empty hard capsules as an input parameter and its potential impact on the finished product quality, a study was performed investigating the critical quality parameters within and in between different batches of empty hard gelatin capsules. The variability of the hard capsules showed high consistency within the specification of the critical quality parameters. This also accounts for the disintegration times, when automatic endpoint detection was used. Based on these data, hard capsules can be considered as a suitable excipient for product development using QbD principles.     

The kinetics of milk coagulation: IV. The kinetics of the gel-firming process

A mechanistic kinetic model of gel firmness development during milk gel formation is presented. The model correctly accounts for the influence of enzymatic kappa-casein hydrolysis on the rate of firmness development in renneted milk gels. The model used is based on two first-order reactions occurring in series. The first reaction is enzymatically controlled and corresponds to the formation of gel crosslink sites by kappa-casein hydrolysis. The second reaction is nonenzymatic and corresponds to the process of crosslink formation and depletion of active sites. The model successfully predicts gel firmness development in the temperature range 31-45 degrees C for a variety of initial enzyme concentrations.     

Mechanistic evaluation of long-term in-stent restenosis based on models of tissue damage and growth

Development and application of advanced mechanical models of soft tissues and their growth represent one of the main directions in modern mechanics of solids. Such models are increasingly used to deal with complex biomedical problems. Prediction of in-stent restenosis for patients treated with coronary stents remains a highly challenging task. Using a finite element method, this paper presents a mechanistic approach to evaluate the development of in-stent restenosis in an artery following stent implantation. Hyperelastic models with damage, verified with experimental results, are used to describe the level of tissue damage in arterial layers and plaque caused by such intervention. A tissue-growth model, associated with vessel damage, is adopted to describe the growth behaviour of a media layer after stent implantation. Narrowing of lumen diameter with time is used to quantify the development of in-stent restenosis in the vessel after stenting. It is demonstrated that stent designs and materials strongly affect the stenting-induced damage in the media layer and the subsequent development of in-stent restenosis. The larger the artery expansion achieved during balloon inflation, the higher the damage introduced to the media layer, leading to an increased level of in-stent restenosis. In addition, the development of in-stent restenosis is directly correlated with the artery expansion during the stent deployment. The correlation is further used to predict the effect of a complex clinical procedure, such as stent overlapping, on the level of in-stent restenosis developed after percutaneous coronary intervention.

     

基于数据库中肺纤维化miRNA及肺癌mRNA芯片资料分析筛查肺癌的潜在治疗靶点

肺癌严重危害人类健康,患者预后较差。肺纤维化是肺癌的危险因素之一,与肺癌的发病机制存在一定关系。肺纤维化中失调的微小RNA(microRNA, miRNA)在肺癌发生发展过程中发挥着重要作用。本研究使用基因表达综合数据库(Gene Expression Omnibus, GEO)中肺纤维化miRNA及肺癌mRNA的芯片数据,利用GEO2R筛选肺纤维化差异miRNA与肺癌差异基因、miRWalk预测miRNA靶基因、STRING分析互作关系、WebGestalt进行GO与KEGG分析、GEPIA分析基因对患者生存的影响,最终获得SNRPE、PIK3R1、ARHGEF6等潜在的肺癌治疗靶点。通过对这些潜在靶点的认识进一步了解肺癌的发生发展机制,为肺癌的临床治疗贡献新的思路。     

斑马鱼心脏发育候选基因Pygo1多克隆抗体的制备及检测

Pygo1是心脏发育候选基因,可能在斑马鱼心脏发育过程中起着重要的调控作用.利用生物信息学选择斑马鱼Pygo1基因抗原亲水区,将扩增出的PCR片段克隆到原核表达pGEMT-4T-1载体中,转入E.coli中后通过IPTG(Isopropylβ-D-thiogalactoside)分别诱导表达GST融合蛋白.蛋白经纯化分离后用于免疫新西兰大白兔制备多克隆抗体.用Western Blot检测抗体的效价和特异性.