BACKGROUND & AIMS: :Iminodisuccinate (IDS) epimerase catalyzes the epimerisation of R,R-, S,S- and R,S- iminodisuccinate, one step in the biodegradation of the chelating agent iminodisuccinate by Agrobacterium tumefaciens BY6. The enzyme is a member of the MmgE/PrpD protein family, a diverse and little characterized class of proteins of prokaryotic and eukaryotic origin. IDS epimerase does not show significant overall amino acid sequence similarity to any other protein of known three-dimensional structure. The crystal structure of this novel epimerase has been determined by multi-wavelength diffraction to 1.5 A resolution using selenomethionine-substituted enzyme. In the crystal, the enzyme forms a homo-dimer, and the subunit consists of two domains. The larger domain, not consecutive in sequence and comprising residues Met1-Lys266 and Leu400-Pro446, forms a novel all alpha-helical fold with a central six-helical bundle. The second, smaller domain folds into an alpha+beta domain, related in topology to chorismate mutase by a circular permutation. IDS epimerase is thus not related in three-dimensional structure to other known epimerases. The fold of the IDS epimerase is representative for the whole MmgE/PrpD family. The putative active site is located at the interface between the two domains of the subunit, and is characterized by a positively charged surface, consistent with the binding of a highly negatively charged substrate such as iminodisuccinate. Docking experiments suggest a two-base mechanism for the epimerisation reaction.

背景与目标： : 亚氨基二琥珀酸酯 (IDS) 差向异构化催化R，R-，S，S-和R，S-亚氨基二琥珀酸酯的差向异构化，这是根癌农杆菌对螯合剂亚氨基二琥珀酸酯生物降解的第一步。该酶是MmgE/PrpD蛋白家族的成员，MmgE/PrpD蛋白家族是原核和真核来源的多种多样且特征很少的蛋白质。IDS差向异构酶与已知三维结构的任何其他蛋白质没有显示出明显的总体氨基酸序列相似性。该新型差向异构酶的晶体结构已通过多波长衍射确定，以使用硒代蛋氨酸取代的酶1.5分辨率。在晶体中，酶形成同型二聚体，亚基由两个结构域组成。较大的结构域不是连续的并且包含Met1-Lys266和Leu400-Pro446的残基，形成具有中心六螺旋束的新型全 α-螺旋折叠。第二个较小的结构域折叠成 α β 结构域，在拓扑上通过环状排列与脉络酸突变酶有关。因此，IDS差向异构酶在三维结构上与其他已知的差向异构酶无关。IDS差向异构酶的折叠代表整个MmgE/PrpD家族。推定的活性位点位于亚基的两个结构域之间的界面处，其特征在于带正电的表面，与高度带负电的底物 (例如亚氨基二琥珀酸酯) 的结合一致。对接实验提出了向异构化反应的两基机制。

BACKGROUND & AIMS: :A computer program is presented which determines the secondary structure of linear RNA molecules by simulating a hypothetical process of folding. This process implies the concept of 'nucleation centres', regions in RNA which locally trigger the folding. During the simulation, the RNA is allowed to fold into pseudoknotted structures, unlike all other programs predicting RNA secondary structure. The simulation uses published, experimentally determined free energy values for nearest neighbour base pair stackings and loop regions, except for new extrapolated values for loops larger than seven nucleotides. The free energy value for a loop arising from pseudoknot formation is set to a single, estimated value of 4.2 kcal/mole. Especially in the case of long RNA sequences, our program appears superior to other secondary structure predicting programs described so far, as tests on tRNAs, the LSU intron of Tetrahymena thermophila and a number of plant viral RNAs show. In addition, pseudoknotted structures are often predicted successfully. The program is written in mainframe APL and is adapted to run on IBM compatible PCs, Atari ST and Macintosh personal computers. On an 8 MHz 8088 standard PC without coprocessor, using STSC APL, it folds a sequence of 700 nucleotides in one and a half hour.

背景与目标： : 提出了一种计算机程序，该程序通过模拟假想的折叠过程来确定线性RNA分子的二级结构。此过程暗示了 “成核中心” 的概念，即RNA中局部触发折叠的区域。在模拟过程中，与所有其他预测RNA二级结构的程序不同，允许RNA折叠成假结结构。模拟使用已发布的，实验确定的最近邻碱基对堆叠和环区域的自由能值，但大于七个核苷酸的环的新外推值除外。由假结形成产生的环的自由能值被设置为4.2 kcal/mole的单个估计值。特别是在长RNA序列的情况下，我们的程序似乎优于迄今为止描述的其他二级结构预测程序，如对trna，嗜热四膜虫的LSU内含子和许多植物病毒RNA的测试所示。此外，伪结网结构通常被成功预测。该程序以大型机APL编写，并适用于在IBM兼容pc，Atari ST和Macintosh个人计算机上运行。在没有协处理器的8 mhz 8088标准PC上，使用stscapl，它在一个半小时内折叠700个核苷酸的序列。

BACKGROUND & AIMS: :Although associated with all plants, fungal endophytes (microfungi that live within healthy plant tissues) represent an unknown proportion of fungal diversity. While there is a growing appreciation of their ecological importance and human uses, little is known about their host specificity, geographic structure, or phylogenetic relationships. We surveyed endophytic Ascomycota from healthy photosynthetic tissues of three plant species (Huperzia selago, Picea mariana, and Dryas integrifolia, representing lycophytes, conifers, and angiosperms, respectively) in northern and southern boreal forest (Québec, Canada) and arctic tundra (Nunavut, Canada). Endophytes were recovered from all plant species surveyed, and were present in <1-41% of 2 mm2 tissue segments examined per host species. Sequence data from the nuclear ribosomal internal transcribed spacer region (ITS) were obtained for 280 of 558 isolates. Species-accumulation curves based on ITS genotypes remained non-asymptotic, and bootstrap analyses indicated that a large number of genotypes remain to be found. The majority of genotypes were recovered from only a single host species, and only 6% of genotypes were shared between boreal and arctic communities. Two independent Bayesian analyses and a neighbor-joining bootstrapping analysis of combined data from the nuclear large and small ribosomal subunits (LSUrDNA, SSUrDNA; 2.4 kb) showed that boreal and arctic endophytes represent Dothideomycetes, Sordariomycetes, Chaetothyriomycetidae, Leotiomycetes, and Pezizomycetes. Many well-supported phylotypes contained only endophytes despite exhaustive sampling of available sequences of Ascomycota. Together, these data demonstrate greater than expected diversity of endophytes at high-latitude sites and provide a framework for assessing the evolution of these poorly known but ubiquitous symbionts of living plants.

背景与目标： : 尽管与所有植物相关，但真菌内生菌 (生活在健康植物组织中的微真菌) 代表了未知的真菌多样性比例。尽管人们越来越认识到它们的生态重要性和人类用途，但对它们的宿主特异性，地理结构或系统发育关系知之甚少。我们调查了北部和南部北方森林 (加拿大魁北克) 和北极苔原 (加拿大努纳武特) 中三种植物 (石杉，云杉，马里亚纳云杉和干草) 的健康光合组织中的内生子囊菌。从调查的所有植物物种中回收内生菌，并且存在于每个宿主物种检查的2平方毫米个组织节段的 <1-41% 中。从核核糖体内部转录间隔区 (ITS) 获得280 558分离株的序列数据。基于其基因型的物种积累曲线仍然是非渐近的，并且bootstrap分析表明仍有大量基因型有待发现。大多数基因型仅从单个宿主物种中回收，并且在北方和北极社区之间仅共享6% 基因型。对来自核大核糖体亚基和小核糖体亚基 (LSUrDNA，SSUrDNA; 2.4 kb) 的合并数据进行了两次独立的贝叶斯分析和邻居连接的自举分析，结果表明，北方和北极内生菌代表独生菌，蛇纹菌，Chaetothyriomycetidae，Leotiomycetes和Pezizomycetes。尽管对子囊菌门的可用序列进行了详尽的采样，但许多支持良好的系统型仅包含内生菌。总之，这些数据证明了高纬度地点内生植物的多样性大于预期，并为评估这些鲜为人知但无处不在的生物共生体的进化提供了一个框架。

BACKGROUND & AIMS: We studied changes in glutamate receptors, expression of immediate early genes, and AP-1 DNA binding activity in the brains of phenobarbital (PB)-dependent and -withdrawn rats to investigate the possible involvement of activation of glutamate receptors in PB withdrawal syndrome. PB-dependent rats were prepared by feeding drug-admixed food for 5 weeks. Autoradiographic analysis showed that binding of [3H(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imin e (MK-801), an antagonist of N-methyl-D-aspartic acid (NMDA) receptors, increased significantly in the cerebral cortices of PB-dependent and 24-h-withdrawn rats. However, [3H]MK-801 binding in the hippocampus and [3H]6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and [3H]kainic acid binding in the hippocampus and cerebral cortex were essentially unchanged in both groups. PB withdrawal seizures were followed by increased expression of c-fos mRNA in the hippocampus and cerebral cortex and of c-jun mRNA in the cerebral cortex. The induction of c-fos and c-jun mRNA was suppressed by administration of MK-801. Furthermore, PB withdrawal enhanced AP-1 DNA binding activity in the brain. The present findings suggest functional enhancement of glutamatergic neurotransmission during the development of PB withdrawal syndrome.

背景与目标： 我们研究了苯巴比妥 (PB) 依赖性和退缩大鼠大脑中谷氨酸受体的变化，即刻早期基因的表达以及AP-1的DNA结合活性，以研究谷氨酸受体激活在PB戒断综合征中的可能参与。通过喂养混合药物的食物5周制备PB依赖性大鼠。放射自显影分析显示，N-甲基-d-天冬氨酸 (NMDA) 受体拮抗剂 [3H(+)-5-甲基-10,11-二氢-5H-二苯并 [a，D] cyclohepten-5，10-敏e (MK-801) 的结合，PB依赖性和24h撤回大鼠的大脑皮层显着增加。然而，[3h] MK-801在海马和 [3H]6-氰基-7-硝基喹喔啉-2结合，海马和大脑皮层中的3-二酮 (CNQX) 和 [3H] 海藻酸结合在两组中基本上没有变化。铅戒断发作后，海马和大脑皮层中c-fos mRNA的表达增加，大脑皮层中c-6月mRNA的表达增加。诱导c-MK-801可抑制fos和c-6月mRNA。此外，铅戒断增强了大脑中的AP-1 DNA结合活性。目前的发现表明，在铅戒断综合征的发展过程中，谷氨酸能神经传递的功能增强。

BACKGROUND & AIMS: PURPOSE:The value of high resolution computed tomography (HR-CT) in the recognition of pathologic changes of the lung parenchyma, especially in the diagnosis of sarcoidosis, is well established. The importance of these findings in regard to the inflammatory activity is not sufficiently documented, also because a direct histologic correlation is seldom possible.

METHOD:In a prospective study twenty-one patients with suspected or known sarcoidosis were evaluated. The diagnostic work up comprised the clinical examination, lung function tests, the radiological evaluation, including GH-CT, and bronchoscopy for bronchoalveolar lavage (BAL) and transbronchial biopsy.

RESULTS:The comparison of the HR-CT findings, like pathologic appearance of the bronchovascular bundle and intraparenchymal nodules, with serologic and BAL-parameters yielded high correlation coefficients with the total cell count in BAL and sIL-2R, and moderate correlations with the lavage lymphocyte count and the activity markers, like T4/T8 ratio, IL-2R and HLA-DR expression.

CONCLUSION:As a non invasive method, HR-CT depicts pathologic findings of the lung parenchyma which are associated with the inflammatory activity of sarcoidosis.

背景与目标： 目的 : 高分辨率计算机断层扫描 (hr-ct) 在识别肺实质的病理变化，特别是在结节病的诊断中的价值已得到充分确立。这些发现在炎症活性方面的重要性尚未得到充分证明，这也是因为很少有直接的组织学相关性。
方法 : 在一项前瞻性研究中，对21例疑似或已知结节病患者进行了评估。诊断工作包括临床检查，肺功能检查，放射学评估 (包括gh-ct) 以及支气管镜检查 (用于支气管肺泡灌洗 (BAL) 和经支气管活检)。
结果 : hr-ct结果的比较，像支气管血管束和实质内结节的病理外观一样，血清学和BAL参数与BAL和sIL-2R的总细胞计数具有高相关系数，与灌洗淋巴细胞计数和活性标志物 (如T4/T8比率) 具有中等相关性，IL-2R和hla-dr表达。
结论 : 作为一种非侵入性方法，hr-ct描述了与结节病的炎症活性相关的肺实质的病理发现。

BACKGROUND & AIMS: Activated neutrophils take a long time to pass through a narrow lumen like a micropore, and are supposed to play a deteriorating effect on microcirculation. Although the activation of neutrophils has been demonstrated in Behçet's disease, nobody analyzes the clinical activity of the disease by means of the rheological measure of neutrophils activity. Using a micropore (pore diameter 5 microns) filtration technique, we measured the filtration time of peripheral blood neutrophils, as a rheological measure of their activity, in order to determine the clinical activity of Behçet's disease. Twenty-one patients with Behçet's disease and 14 healthy control individuals were enrolled in the study. Symptoms and signs exhibited in the patients led us to distinguish the Behçet's disease into inactive and active cases. The latter were further differentiated into cases with absent symptoms and with present symptoms. Neutrophil filtration times were 11.5 +/- 4.8 s in the active cases with present symptoms, which were significantly (P < 0.05) larger than those (7.4 +/- 1.9 s) in the active cases with absent symptoms. The latter filtration times were further significantly (P < 0.001) larger than values (3.7 +/- 1.3 s) in the inactive cases and also those (4.8 +/- 1.2 s) in control subjects. Furthermore, increases in the filtration time obtained immediately after the exposure of cells to the chemotactic peptide formyl-methionyl-leucyl-phenylalanine (FMLP10 nM) were significantly (P < 0.01) larger in the active cases with present symptoms than those in the active cases with absent symptoms. The latter were also larger, but not significantly, than those in the inactive cases, and were significantly (P < 0.01) larger than those in control subjects. The present results demonstrate that the micropore filtration method reflects well the rheological activity of neutrophils as well as the clinical status of Behçet's disease. This method is much better than the measurement of O2 production to differentiate between active cases with absent symptoms and inactive patients or even control individuals. Furthermore, it is more sensitive and useful than laboratory data like the CRP value or the number of peripheral blood neutrophils.

背景与目标： 活化的中性粒细胞需要很长时间才能通过像微孔一样的狭窄管腔，并且应该对微循环起到恶化的作用。尽管在beh ç et病中已经证明了中性粒细胞的激活，但没有人通过中性粒细胞活性的流变学测量来分析该疾病的临床活性。使用微孔 (孔径5微米) 过滤技术，我们测量了外周血中性粒细胞的过滤时间，作为其活性的流变学指标，以确定白塞氏病的临床活性。21名beh ç et病患者和14名健康对照者参加了这项研究。患者表现出的症状和体征使我们将白塞氏病区分为不活跃和活跃的病例。后者进一步分为无症状和现有症状的病例。有症状的活动病例的中性粒细胞过滤时间为11.5 +/- 4.8 s，显著 (P < 0.05) 大于无症状的活动病例的中性粒细胞过滤时间 (7.4 +/- 1.9 s)。后者的过滤时间进一步显著 (P < 0.001) 大于非活性情况下的值 (3.7 +/- 1.3 s)，也大于对照受试者中的值 (4.8 +/- 1.2 s)。此外，在细胞暴露于趋化肽甲酰基-甲硫酰基-亮氨酸-苯丙氨酸 (fmlp10nm) 后立即获得的过滤时间的增加在存在症状的活动病例中比在不存在症状的活动病例中显着 (P < 0.01) 大。后者也比不活跃的情况更大，但不显著，并且显著 (P < 0.01) 大于对照组。目前的结果表明，微孔过滤方法很好地反映了嗜中性粒细胞的流变活性以及白塞病的临床状况。此方法比O2产生的测量要好得多，可以区分无症状的活跃病例和不活跃的患者甚至对照组。此外，它比CRP值或外周血中性粒细胞数量等实验室数据更敏感和有用。

BACKGROUND & AIMS: Marked increases in case rates of drug-resistant tuberculosis and nontuberculous mycobacterial infections have brought renewed urgency to the development of new treatment regimens for mycobacterial infections. Preclinical data, such as in vitro measures of drug activity and pharmacokinetics, are used in the design of new treatment regimens. This review surveys the extensive published clinical experience concerning the treatment of drug-susceptible tuberculosis to evaluate the use of these preclinical measures in predicting clinical outcomes of antimycobacterial therapy. In vitro measures of drug activity predict the potency of a drug to prevent the emergence of resistance to other antimycobacterial drugs but do not predict the sterilizing activity of a drug or the activity of drug combinations. In vitro measures of drug activity do not allow reliable predictions of the level at which an organism should be considered resistant. Assays of drug penetration in tissues and activity against intracellular bacilli add modestly to the predictive value of in vitro measures of drug activity but still do not predict sterilizing activity. In contrast, animal models of tuberculosis have predicted relative drug potency (including sterilizing activity), the efficacy of multidrug regimens, and the duration of therapy needed. Despite pharmacokinetic parameters that would suggest the need for multiple doses per day, all of the first-line antituberculous drugs are active when given as infrequently as twice weekly. It is difficult to predict the efficacy of therapy for an intracellular pathogen that has the capacity for dormancy. Better in vitro models are needed, particularly ones that predict sterilizing activity.

背景与目标： 耐药结核病和非结核分枝杆菌感染的病例率显着增加，为开发新的分枝杆菌感染治疗方案带来了新的紧迫性。临床前数据，例如药物活性和药代动力学的体外测量，用于设计新的治疗方案。这篇综述调查了有关药物敏感结核病治疗的广泛已发表的临床经验，以评估这些临床前措施在预测抗细菌治疗临床结果中的应用。药物活性的体外测量可以预测药物的效力，以防止对其他抗细菌药物的耐药性出现，但不能预测药物的灭菌活性或药物组合的活性。药物活性的体外测量无法可靠地预测生物体应被认为具有抗性的水平。药物在组织中的渗透和对细胞内杆菌的活性的测定适度增加了药物活性的体外测量的预测值，但仍不能预测灭菌活性。相反，结核病的动物模型已经预测了相对的药物效力 (包括灭菌活性)，多药疗法的功效以及所需的治疗持续时间。尽管药代动力学参数表明每天需要多次剂量，但所有一线抗结核药物在每周两次的情况下均具有活性。很难预测具有休眠能力的细胞内病原体的治疗效果。需要更好的体外模型，尤其是可以预测灭菌活性的模型。

BACKGROUND & AIMS: :The nature of the temporal relationship between antibacterial consumption and Streptococcus pneumoniae penicillin resistance is investigated using population level data across time. IMS Health Global Services provided national outpatient antibiotic prescription data for the years 1996-2003 from France, Spain, Italy, Germany, the United Kingdom, and the United States. Surveillance data consist of S. pneumoniae isolates obtained from a surveillance database in the same geographic regions from 1996 to 2003. A linear mixed model for repeated measures was used to analyze the association between resistance and several antibacterial classes through time. Changes in penicillin resistance through time in any country are better explained by the weighted cumulative antibacterial consumption with a 2-year lag. Narrow-spectrum penicillins are associated with lower resistance rates. Large reductions in consumption at the population level are needed to affect resistance. There is a peak level of penicillin resistance associated with cumulative exposure to a combination of antibiotic classes that is unique for every country.

背景与目标： : 使用跨时间的人群水平数据研究了抗菌药物消耗与肺炎链球菌青霉素耐药性之间的时间关系的性质。IMS Health Global Services提供了来自法国，西班牙，意大利，德国，英国和美国的1996-2003年全国门诊抗生素处方数据。监视数据由从2003年1996年相同地理区域的监视数据库中获得的肺炎链球菌分离株组成。使用用于重复测量的线性混合模型来分析耐药性与几种抗菌剂之间的关系。在任何国家，青霉素耐药性随时间的变化都可以通过滞后2年的加权累积抗菌药物消耗量来更好地解释。窄谱青霉素与较低的耐药率相关。为了影响抵抗力，需要大量减少人口消费。青霉素耐药性的峰值水平与累积暴露于抗生素类别的组合有关，这在每个国家都是独一无二的。

BACKGROUND & AIMS: Neural activity is thought to play a significant role during the development of the cerebral cortex. In this study, we examined the effects of global activity block or enhancement and the effects of patterned firing on the ability of cultured rat neocortical neurons to survive during the second week in vitro, beyond the beginning of synaptogenesis. Blockade of neuronal activity by adding tetrodotoxin (TTX) and increasing magnesium concentration in the medium strongly reduced the survival of cortical cells. Increasing neuronal activity by raising the external potassium concentration significantly improved the survival of cortical neurons. We postulated that in a developing neuronal network the survival of nerve cells is regulated by synaptically mediated events that involve changes in the intracellular calcium concentration. To examine this question further, we monitored the activity of the developing network by optically recording the intracellular calcium signals of many neurons simultaneously. These recordings show that in low magnesium neocortical neurons express synchronized oscillation of their intracellular calcium concentration. The ability of a network to synchronize the changes in intracellular calcium of multiple cells appeared gradually during the second week in culture, paralleled by both an increase in the synaptic density and a decline in the number of surviving neurons. By examining the fate of identified cells several days after a recording session, we found that those nerve cells that were co-activated with other neurons had a significantly higher chance to survive than cells that did not participate in synchronized events. These experiments demonstrate that during early cortical network development cortical neurons show synchronized firing activity and that the survival of neurons is at least partially dependent on this pattern of neuronal activity.

背景与目标： 神经活动被认为在大脑皮层发育过程中起着重要作用。在这项研究中，我们研究了整体活动阻滞或增强的影响以及图案化放电对培养的大鼠新皮层神经元在体外第二周 (突触开始后) 存活的能力的影响。通过添加河豚毒素 (TTX) 和增加培养基中的镁浓度来阻断神经元活性，从而大大降低了皮质细胞的存活。通过提高外部钾浓度来增加神经元活性，显着改善了皮质神经元的存活。我们推测，在发育中的神经元网络中，神经细胞的存活受到突触介导的事件的调节，这些事件涉及细胞内钙浓度的变化。为了进一步研究这个问题，我们通过同时光学记录许多神经元的细胞内钙信号来监测发育网络的活动。这些记录表明，在低镁的新皮层神经元中，其细胞内钙浓度表达同步振荡。在培养的第二周，网络使多个细胞的细胞内钙的变化同步的能力逐渐出现，同时突触密度增加和存活神经元数量减少。通过在记录过程几天后检查已识别细胞的命运，我们发现与其他神经元共同激活的神经细胞比不参与同步事件的细胞存活的机会要高得多。这些实验表明，在早期皮质网络发育过程中，皮质神经元显示出同步的放电活动，并且神经元的存活至少部分取决于这种神经元活动模式。

BACKGROUND & AIMS: :Crossing of the pleurovisceral nerve cords in gastropods has supported the view that gastropods evolved by 180 degrees rotation between the ventral and dorsal body regions. Indeed, a rotation of this type occurs as a dramatic morphogenetic movement ("ontogenetic torsion") during the development of basal gastropods. According to a long-standing hypothesis, ontogenetic torsion in basal gastropods preserves an ancient developmental aberration that generated the contorted gastropod body plan. It follows from this reasoning that crossing of the pleurovisceral nerve cords during gastropod development should be mechanically coupled to ontogenetic torsion. The predicted mechanical coupling can now be examined because of the discovery of an early differentiating neuron in Haliotis kamtschatkana (Vetigastropoda) that expresses 5-hydroxytryptamine-like immunoreactivity. The neuron appeared to delineate the trajectory of the pleurovisceral nerve cords beginning before ontogenetic torsion. Before torsion, the neuronal soma is embedded in mantle epithelium at the ventral midline and two neurites extend anteriorly toward the apical sensory organ. Contrary to expectation, the two neurites of this cell did not cross-over during ontogenetic torsion because the soma of this mantle neuron shifted in the same direction as the rotating head and foot. Full crossing of the pleurovisceral nerve cords occurred gradually during later development as the mantle cavity deepened and expanded leftward. These results are consistent with a generalization emerging from comparative studies indicating a conserved developmental stage for gastropods in which the mantle cavity is localized to one side, despite a fully "post-torsional" orientation for other body components. Developmental morphology before this stage is much more variable among different gastropod clades.

背景与目标： 腹足动物胸膜内脏神经索的交叉支持了腹足动物通过腹侧和背侧身体区域之间180度旋转而进化的观点。实际上，在基础腹足类动物的发育过程中，这种类型的旋转是一种戏剧性的形态发生运动 (“个体发生扭转”)。根据长期存在的假设，基础腹足动物的个体发育扭转保留了古老的发育畸变，该畸变产生了扭曲的腹足动物身体计划。从这种推理可以得出，腹足动物发育过程中胸膜内脏神经索的交叉应与个体发生扭转机械耦合。现在可以检查预测的机械耦合，因为在Haliotis kamtschatkana (Vetigastropoda) 中发现了表达5-羟色胺样免疫反应性的早期分化神经元。神经元似乎描绘了个体发生扭转之前开始的胸膜内脏神经索的轨迹。在扭转之前，神经元躯体嵌入腹侧中线的套膜上皮中，两个神经突向前向顶端感觉器官延伸。与预期相反，该细胞的两个神经突在个体发生扭转期间没有交叉，因为该套神经元的躯体与旋转的头和脚沿相同的方向移动。在后来的发育过程中，随着地幔腔的加深和向左扩展，胸膜内脏神经索的完全交叉逐渐发生。这些结果与比较研究得出的概括一致，该比较研究表明腹足类动物处于保守的发育阶段，尽管其他身体成分完全处于 “扭转后” 方向，但地幔腔仍位于一侧。不同腹足纲进化枝在此阶段之前的发育形态变化更大。

BACKGROUND & AIMS: :Cyproheptadine is a drug that shows high affinity for type 2 (5-HT2) receptors. We studied a series of compounds obtained by modification of the tricyclic system of Cyp (dibenzocycloheptadiene): 2f (thioxanthene), 2g (xanthene), 2h (dihydrodibenzocycloheptadiene), 2j (diphenyl), 2i (fluorene), and 3b (phenylmethyl). Their activities at the rat cerebral cortex 5-HT2A receptor were (pKi +/- S.E.M.): 8.80 +/- 0.11 (Cyp), 8.60 +/- 0.07 (2f), 8.40 +/- 0.02 (2g), 8.05 +/- 0.03 (2h), 7.87 +/- 0.12 (2j), 6.70 +/- 0.02 (2i) and 6.45 +/- 0.02 (3b); those at the rat stomach fundus 5-HT2B receptor (pA2 +/- S.E.M.) were: 9.14 +/- 0.25 (Cyp), 8.49 +/- 0.07 (2f), 7.58 +/- 0.58 (2g), 7.02 +/- 0.14 (2h), 6.07 +/- 0.20 (2j), and undetectable (2i, 3b): and those at the pig choroidal plexus 5-HT2C receptor (pKi +/- S.E.M.) were: 8.71 +/- 0.08 (Cyp), 8.68 +/- 0.01 (2f), 8.58 +/- 0.20 (2g), 7.95 +/- 0.05 (2h), 7.57 +/- 0.04 (2j), 6.98 +/- 0.04 (2i) and 6.63 +/- 0.20 (3b). The slopes did not differ significantly from unity. The compounds exhibited the same order of activities at every type of receptor, and the most active molecules presented certain steric (butterfly conformation of the tricyclic system) and electrostatic (proton affinity on the top of the central rings) patterns. It is concluded that the activity of cyproheptadine derivatives at 5-HT2 receptors is related to these molecular features, which make feasible a common disposition to interact with all three 5-HT2 subtypes.

背景与目标： : 赛庚胺是一种对2型 (5-HT2) 受体显示高亲和力的药物。我们研究了通过修饰Cyp (二苯并环庚二烯) 的三环体系获得的一系列化合物: 2f (噻吩)，2g (xanthene)，2h (二氢二苯并环庚二烯)，2j (二苯基)，2i (芴) 和3b (苯基甲基)。它们在大鼠大脑皮层5-HT2A受体上的活性为 (pKi +/-s.e.M.): 8.80 +/- 0.11 (Cyp)，8.60 +/- 0.07 (2f)，8.40 +/- 0.02 (2g)，8.05 +/- 0.03 (2h)，7.87 +/- 0.12 (2j)，6.70 +/- 0.02 (2i) 和6.45 +/- 0.02 (3b); 大鼠胃底5-HT2B受体 (pA2 +/-s.e.M.) 为: 9.14 +/- 0.25 (Cyp)，8.49 +/- 0.07 (2f)，7.58 +/- 0.58 (2g)，7.02 +/- 0.14 (2h)，6.07 +/- 0.20 (2j) 和不可检测 (2i，3b): 猪脉络丛5-HT2C受体 (pKi +/-s.e.M.) 为: 8.71 +/- 0.08 (Cyp)，8.68 +/- 0.01 (2f)，8.58 +/- 0.20 (2g)，7.95 +/- 0.05 (2h) 、7.57 +/- 0.04 (2j) 、6.98 +/- 0.04 (2i) 和6.63 +/- 0.20 (3b)。坡度与统一没有显着差异。这些化合物在每种类型的受体上都表现出相同的活性顺序，并且最具活性的分子呈现某些空间 (三环系统的蝴蝶构象) 和静电 (中心环顶部的质子亲和力) 模式。结论是，赛庚胺衍生物在5-HT2受体上的活性与这些分子特征有关，这使得与所有三种5-HT2亚型相互作用的共同处置是可行的。

BACKGROUND & AIMS: :6-Pyruvoyltetrahydropterin synthase (PTPS) catalyzes the second step of tetrahydrobiopterin (BH4) synthesis. We previously identified PTPS orthologs (bPTPS-Is) in bacteria which do not produce BH4. In this study we disrupted the gene encoding bPTPS-I in Synechococcus sp. PCC 7942, which produces BH4-glucoside. The mutant was normal in BH4-glucoside production, demonstrating that bPTPS-I does not participate in BH4 synthesis in vivo and bringing us a new PTPS ortholog (bPTPS-II) of a bimodular polypeptide. The recombinant Synechococcus bPTPS-II was assayed in vitro to show PTPS activity higher than human enzyme. Further computational analysis revealed the presence of mono and bimodular bPTPS-II orthologs mostly in green sulfur bacteria and cyanobacteria, respectively, which are well known for BH4-glycoside production. In summary we found new bacterial PTPS orthologs, having either a single or dual domain structure and being responsible for BH4 synthesis in vivo, thereby disclosing all the bacterial PTPS homologs.

背景与目标： : 6-丙酮酸基四氢蝶呤合酶 (PTPS) 催化四氢生物蝶呤 (BH4) 合成的第二步。我们先前在不产生bh4的细菌中鉴定了PTPS直系同源物 (bPTPS-Is)。在这项研究中，我们破坏了Synechococcus sp. PCC 7942中编码bPTPS-I的基因，该基因产生了BH4-glucoside。该突变体在BH4-glucoside生产中是正常的，表明bPTPS-I在体内不参与BH4合成，并为我们带来了双峰多肽的新PTPS直系同源物 (bPTPS-II)。在体外测定了重组Synechococcus bptp-II，显示PTPS活性高于人酶。进一步的计算分析表明，分别在绿色硫细菌和蓝细菌中存在单和双模bPTPS-II直系同源物，这在BH4-glycoside生产中是众所周知的。总而言之，我们发现了新的细菌PTPS直系同源物，具有单个或双结构域结构，并负责体内BH4的合成，从而公开了所有细菌PTPS同源物。

BACKGROUND & AIMS: :The role of carbohydrate in the antigenic and immunogenic structure of bovine herpesvirus type 1 (BHV-1) glycoproteins gI and gIV was investigated. Deglycosylated proteins induced a significantly lower antibody response in rabbits than native glycoproteins suggesting that the immunogenicity of several epitopes on gI and gIV is carbohydrate-dependent. Loss of carbohydrate from gI also resulted in a significantly decreased ability to induce a serum neutralizing antibody response to BHV-1, due to modifications in three distinct carbohydrate-containing continuous epitopes. Similarly, in vitro lysis of BHV-1-infected cells was significantly reduced when antibodies raised against deglycosylated gI were employed; this was attributed to changes in two of the three carbohydrate-dependent neutralizing epitopes on gI. The oligosaccharides may be directly involved as actual components of these continuous epitopes, rather than in stabilization of the conformation of the protein. In contrast, carbohydrate removal from gIV did not have a significant effect on the capacity to stimulate a neutralizing antibody response. Accordingly, none of the neutralizing epitopes on gIV appeared to be carbohydrate-dependent. Similarly, lysis of virus-infected cells was not significantly reduced when antibodies specific for deglycosylated rather than native gIV were used. In contrast to the humoral response, the delayed-type hypersensitivity response was stronger in rabbits immunized with deglycosylated proteins than in those inoculated with native glycoproteins gI or gIV. Consequently, the carbohydrates on gI and gIV may play a dual role in the host's immune recognition and response by contributing to certain epitopes, but masking others. The implications for the development of a subunit vaccine against BHV-1 are discussed.

背景与目标： : 研究了碳水化合物在牛疱疹病毒1型 (BHV-1) 糖蛋白gI和gIV的抗原性和免疫原性结构中的作用。与天然糖蛋白相比，去糖基化蛋白诱导的兔抗体反应明显降低，这表明gI和gIV上几个表位的免疫原性是碳水化合物依赖性的。由于三个不同的含碳水化合物的连续表位的修饰，gI中碳水化合物的损失还导致诱导血清中和抗体对BHV-1的反应的能力显着降低。同样，当使用抗去糖基化gI的抗体时，BHV-1-infected细胞的体外裂解显着减少; 这归因于gI上三个碳水化合物依赖性中和表位中的两个的变化。寡糖可能直接作为这些连续表位的实际成分参与，而不是稳定蛋白质的构象。相反，从gIV中去除碳水化合物对刺激中和抗体反应的能力没有显着影响。因此，gIV上的中和表位似乎都不是碳水化合物依赖性的。同样，当使用对去糖基化而非天然gIV具有特异性的抗体时，病毒细胞的裂解也没有显着减少。与体液反应相反，用去糖基化蛋白免疫的兔子的迟发型超敏反应比用天然糖蛋白gI或gIV接种的兔子更强。因此，gI和gIV上的碳水化合物可能通过促进某些表位而在宿主的免疫识别和反应中起双重作用，但掩盖了其他表位。讨论了开发针对BHV-1的亚单位疫苗的意义。

BACKGROUND & AIMS: :Attention-deficit hyperactivity disorder (ADHD) is a common childhood psychiatric disorder. Despite intensive research efforts, the aetiology of ADHD remains unknown. Current evidence suggests that the aetiology of ADHD is heterogeneous, comprising of multiple factors. Recently, it has been proposed that brain-derived neurotrophic factor (BDNF), a member of the neurotrophic factor family, may be implicated in the pathogenesis of ADHD. This hypothesis is supported by recent genetic studies in ADHD. Drawing on findings from studies into the drugs for ADHD relating to central BDNF expression, hyperactivity in BDNF knockout mice, BDNF effects in midbrain dopaminergic function and the close association between BDNF and the dopamine transporter (an important molecule for ADHD pathogenesis), it is proposed here that decreased central BDNF, particularly in the midbrain region, may play an important role in the pathogenesis ADHD. This hypothesis may have some implications for clinical findings in ADHD (for example, the co-morbidity between ADHD and major depression), and provide a new direction for the development of medication for ADHD treatment.

背景与目标： : 注意力缺陷多动障碍 (ADHD) 是一种常见的儿童精神疾病。尽管进行了大量研究，但ADHD的病因仍然未知。目前的证据表明，ADHD的病因是异质的，由多种因素组成。最近，有人提出，神经营养因子家族的成员脑源性神经营养因子 (BDNF) 可能与ADHD的发病机理有关。该假设得到了ADHD最近的遗传研究的支持。根据对ADHD药物的研究结果，该药物与中枢BDNF表达，BDNF基因敲除小鼠的活动过度，BDNF在中脑多巴胺能功能中的作用以及BDNF与多巴胺转运蛋白 (ADHD发病机理的重要分子) 之间的密切联系有关，在这里提出降低中枢BDNF，特别是在中脑区域，可能在ADHD的发病机理中起重要作用。该假设可能对ADHD的临床发现 (例如，ADHD与重度抑郁症之间的合并症) 具有一定的意义，并为ADHD治疗药物的发展提供了新的方向。

BACKGROUND & AIMS: PURPOSE:Consistent condom use is critical to efforts to prevent sexually transmitted infections among adolescents, but condom use may decline as relationships and contraceptive needs change. The purpose of this research is to assess changes in condom non-use longitudinally in the context of changes in relationship quality, coital frequency and hormonal contraceptive choice. METHODS:Participants were women (aged 14-17 years at enrollment) recruited from three urban adolescent medicine clinics. Data were collected at three-month intervals using a face-to-face structured interview. Participants were able to contribute up to 10 interviews, but on average contributed 4.2 interviews over the 27-month period. Independent variables assessed partner-specific relationship quality (five items; scale range 5-25; alpha = .92, e.g., this partner is a very important person to me); and, number of coital events with a specific partner. Additional items assessed experience with oral contraceptive pills (OCP) use and injected depo medroxy-progesterone acetate (DMPA). The outcome variable was number of coital events without condom use during the past three months. Analyses were conducted as a three-level hierarchical linear growth curve model using HLM 6. The Level 1 predictor was time, to test the hypothesis that condom non-use increases over time. Level 2 predictors assessed relationship quality and coital frequency across all partners to assess hypotheses that participants' condom non-use increases over time as a function of relationship quality and coital frequency. Level 3 predictors assessed the participant-level influence of OCP or DMPA experience on time-related changes in condom non-use. RESULTS:A total of 176 women reported 279 sex partners and contributed 478 visits. Both average coital frequency and average condom non-use linearly increased during the 27-month follow-up. At any given follow-up, about 35% reported recent OCP use, and 65% reported DMPA use. HLM analyses showed that condom non-use increased as a function of time (beta = .12; p = .03, Level 1 analysis). Increased condom non-use over time was primarily a function of increased coital frequency (beta = .01; p = .00), although higher levels of relationship quality were associated with increased condom non-use at enrollment (beta = .44; p = .00, Level 2 analysis). The temporal rise in condom non-use significantly increased among DMPA users (beta = .06; p = .00) but not OCP users (Level 3 analysis) (beta = -.04; p = .06). CONCLUSIONS:Developmentally, relationship characteristics and coital frequency appear to have increasing weight in decisions about condom use. Hormonal contraceptive methods are not equivalently associated with the overall temporal decline in condom use. Future research associated with dual contraceptive/condom use should address differential factors associated condom use in combination with different hormonal methods.

背景与目标：