BACKGROUND & AIMS: :Foxp3 has been shown to be both necessary and sufficient for the development and function of naturally arising CD4+ CD25+ regulatory T cells in mice. Mutation of Foxp3 in Scurfy mice and FOXP3 in humans with IPEX results in fatal, early onset autoimmune disease and demonstrates the critical role of FOXP3 in maintaining immune homeostasis. The FOXP3 protein encodes several functional domains, including a C2H2 zinc finger, a leucine zipper, and a winged-helix/forkhead (FKH) domain. We have shown previously that FOXP3 functions as a transcriptional repressor and inhibits activation-induced IL-2 gene transcription. To characterize the role of each predicted functional domain on the in vivo activity of FOXP3, we have evaluated the location of point mutations identified in a large cohort of patients with the immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) and found them to cluster primarily within the FKH domain and the leucine zipper, but also present within the poorly defined N-terminal portion of the protein. The molecular functions of each of the IPEX-targeted domains were investigated. We show that FOXP3 is constitutively localized to the nucleus and this localization requires sequences at both the amino and C-terminal ends of its FKH domain. Moreover, FOXP3 was found to homodimerize through its leucine zipper. We also identify a novel functional domain within the N-terminal half of FOXP3, which is required for FOXP3-mediated repression of transcription from both a constitutively active and a NF-AT-inducible promoter. Furthermore, we demonstrate that IPEX mutations in these domains correlate with deficiencies in FOXP3 repressor function, corroborating their in vivo relevance.

背景与目标： : Foxp3已被证明对于小鼠中自然产生的CD4 CD25调节性T细胞的发育和功能既必要又充分。在患有pex的Scurfy小鼠中Foxp3和人类中FOXP3的突变会导致致命的，早发性自身免疫性疾病，并证明了FOXP3在维持免疫稳态中的关键作用。FOXP3蛋白编码几个功能结构域，包括C2H2锌指，亮氨酸拉链和有翼螺旋/叉头 (FKH) 结构域。我们先前已经证明FOXP3作为转录阻遏物起作用并抑制激活诱导的IL-2基因转录。为了表征每个预测的功能域对FOXP3体内活性的作用，我们评估了在免疫失调，多内分泌病，肠病，X连锁综合征 (IPEX)，发现它们主要聚集在FKH结构域和亮氨酸拉链内，但也存在于蛋白质定义不明确的N端部分。研究了每个pex靶向域的分子功能。我们证明FOXP3组成性地定位于细胞核，并且这种定位需要在其FKH结构域的氨基和C末端都具有序列。此外，发现FOXP3通过其亮氨酸拉链同向二聚。我们还在FOXP3的N末端一半内鉴定了一个新的功能结构域，这是FOXP3-mediated抑制组成型活性和NF-AT诱导启动子转录所必需的。此外，我们证明了这些域中的IPEX突变与FOXP3阻遏物功能的缺陷相关，从而证实了它们在体内的相关性。

BACKGROUND & AIMS: :We show that STAT5b is important for the in vivo accumulation of CD4+ CD25(high) T cells with regulatory cell function. A patient homozygous for a missense A630P STAT5b mutation displayed immune dysregulation and decreased numbers of CD4+ CD25(high) T cells. STAT5b(A630P/A630P) CD4+ CD25(high) T cells had low expression of forkhead box P3 and an impaired ability to suppress the proliferation of or to kill CD4+ CD25- T cells. Expression of CD25, a component of the high-affinity IL-2R, was also reduced in response to IL-2 or after in vitro propagation. The impact of the STAT5b mutation was selective in that IL-2-mediated up-regulation of the common gamma-chain cytokine receptor and perforin, and activation-induced expressions of CD154 and IFN-gamma were normal. These results indicate that STAT5b propagates an important IL-2-mediated signal for the in vivo accumulation of functional regulatory T cells.

背景与目标： : 我们显示STAT5b对于具有调节细胞功能的CD4 CD25 (高) T细胞的体内积累很重要。一名因错义A630P STAT5b突变而纯合的患者表现出免疫失调和CD4 CD25 (高) T细胞数量减少。STAT5b(A630P/A630P) CD4 CD25 (高) T细胞的叉头盒P3表达低，抑制或杀死CD4 cd25-t细胞的增殖能力受损。高亲和力IL-2R的组分CD25的表达也在响应IL-2或体外繁殖后降低。STAT5b突变的影响是选择性的，因为IL-2-mediated常见的 γ 链细胞因子受体和穿孔素的上调，并且激活诱导的CD154和IFN-γ 的表达正常。这些结果表明STAT5b传播了功能性调节性T细胞在体内积累的重要IL-2-mediated信号。

BACKGROUND & AIMS: :The oncoprotein LMP1 mimics an activated CD40 receptor, yet it is not known whether constitutive CD40 signaling, like LMP1, is sufficient to transform cells. Here we demonstrate that constitutive activation of the CD40 pathway by a chimeric LMP1CD40 molecule resembles the transforming function of LMP1 in inducing loss of contact inhibition and anchorage independent growth of Rat1 fibroblasts. Rat1 transformation correlates with the expression level of LMP1CD40 and depends on its ability to oligomerize. Our data provide direct evidence for the oncogenic potential of the CD40 signaling pathway, which is also established as a model-mechanism for LMP1-induced transformation.

背景与目标： : 癌蛋白LMP1模仿活化的CD40受体，但尚不清楚组成型CD40信号传导 (如LMP1) 是否足以转化细胞。在这里，我们证明了嵌合LMP1CD40分子对CD40途径的组成型激活类似于LMP1在诱导Rat1成纤维细胞的接触抑制丧失和锚定独立生长方面的转化功能。Rat1转化与LMP1CD40的表达水平相关，并取决于其寡聚能力。我们的数据为CD40信号通路的致癌潜力提供了直接证据，CD40信号通路也被确立为LMP1-induced转化的模型机制。

BACKGROUND & AIMS: BACKGROUND:The combination of inhaled corticosteroids (ICS) and long-acting beta2-agonists (LABA) is recommended by treatment guidelines for the treatment of persistent asthma. Two such combination products, salmeterol/fluticasone propionate (SFC, Seretide GSK, UK) and formoterol/budesonide (FBC, Symbicort, AstraZeneca, UK) are commercially available. OBJECTIVES:The purpose of these studies was to evaluate and compare the duration of bronchodilation of both combination products up to 24 hours after a single dose. METHODS:Two randomised, double blind, placebo-controlled, crossover studies were performed. Study A was conducted in 33 asthmatic adults receiving 400-1200 mcg of budesonide or equivalent. Serial forced expiratory volume in one second (FEV1) was measured over 24 hours to determine the duration of effect of both SFC (50/100 mcg) and FBC (4.5/160 mcg). Study B was conducted in 75 asthmatic adults receiving 800-1200 mcg of budesonide or equivalent and comprised a 4 week run-in of 400 mcg bd Becotide followed by 4 weeks treatment with either SFC 50/100 mcg bd or FBC 4.5/160 mcg bd taken in a cross-over manner. Serial 24-hour FEV1 was measured after the first dose and the last dose after each 4-weeks treatment period to determine the offset of action of each treatment. RESULTS:In study A, a single inhalation of SFC and FBC produced a sustained bronchodilation at 16 hours with an adjusted mean increase in FEV1 from pre-dose of 0.22 L (95% CI 0.19, 0.35 L) for SFC and 0.25 L (95% CI 0.21, 0.37 L) for FBC, which was significantly greater than placebo for both treatments (-0.05 L; p < 0.001). In study B, the slope of decline in FEV1 from 2-24 hours post dose was -16.0 ml/hr for SFC and -14.2 ml/hr for FBC. The weighted mean AUC over 24 hours was 0.21 Lxmin and 0.22 Lxmin and mean change from pre-dose FEV1 at 12 hours was 0.21 L for SFC and 0.20 L for FBC respectively CONCLUSION:Both SFC and FBC produced a similar sustained bronchodilator effect which was prolonged beyond 12 hours post dose and was clearly measurable at 24 h.

背景与目标：

BACKGROUND & AIMS: :Cyclic and congenital neutropenia are caused by mutations in the human neutrophil elastase (HNE) gene (ELA2), leading to an immunodeficiency characterized by decreased or oscillating levels of neutrophils in the blood. The HNE mutations presumably cause loss of enzyme activity, consequently leading to compromised immune system function. To understand the structural basis for the disease, we implemented methods from bioinformatics to analyze all the known HNE missense mutations at both the sequence and structural level. Our results demonstrate that the 32 different mutations have diverse effects on HNE structure and function, affecting structural disorder and aggregation tendencies, stability maintaining contacts, and electrostatic properties. A large proportion of the mutations are located at conserved amino acids, which are usually essential in determining protein structure and function. The majority of the disease-causing HNE missense mutations lead to major structural changes and loss of stability in the protein. A few mutations also affect functional residues, leading into decreased catalytic activity or altered ligand binding. Our analysis reveals the putative effects of all known missense mutations in HNE, thus allowing the structural basis of cyclic and congenital neutropenia to be elucidated. We have employed and analyzed a set of some 30 different methods for predicting the effects of amino acid substitutions. We present results and experience from the analysis of the applicability of these methods in the analysis of numerous genes, proteins, and diseases to reveal protein structure-function relationships and disease genotype-phenotype correlations.

背景与目标： : 周期性和先天性中性粒细胞减少症是由人类中性粒细胞弹性蛋白酶 (HNE) 基因 (ELA2) 突变引起的，导致免疫缺陷，其特征是血液中中性粒细胞水平降低或振荡。HNE突变可能会导致酶活性丧失，从而导致免疫系统功能受损。为了了解疾病的结构基础，我们采用了生物信息学的方法，在序列和结构水平上分析了所有已知的HNE错义突变。我们的结果表明，32种不同的突变对HNE的结构和功能具有不同的影响，影响结构紊乱和聚集趋势，保持接触的稳定性和静电特性。大部分突变位于保守的氨基酸，这通常是确定蛋白质结构和功能的关键。大多数引起疾病的HNE错义突变会导致蛋白质的主要结构变化和稳定性丧失。一些突变也会影响功能残基，导致催化活性降低或配体结合改变。我们的分析揭示了HNE中所有已知的错义突变的推定作用，从而阐明了周期性和先天性中性粒细胞减少症的结构基础。我们已经采用并分析了一组30种不同的方法来预测氨基酸取代的影响。我们介绍了这些方法在众多基因，蛋白质和疾病分析中的适用性分析的结果和经验，以揭示蛋白质结构-功能关系和疾病基因型-表型相关性。

BACKGROUND & AIMS: Low intensity ultrasound signals, similar to that employed in clinical therapy, are found to mediate differential gene transfer and expression of the Green Fluorescence Protein (GFP) reporter in two human prostate cancer cell lines, LnCap and PC-3. Cell suspensions in the presence or in the absence of GFP (44.5nM) were treated at 37 degrees C under a standing wave condition. Cells were exposed to either continuous wave, 932.7kHz ultrasound, or to several independent bursts, each burst comprising a 20% duty cycle (932.7kHz) sine wave. The burst "repetition" frequency was varied from 10Hz to 10kHz in several different experiments and each treatment received a net identical ultrasound energy exposure. Transient GFP expression levels in viable cells were monitored by flow cytometry. The findings revealed a strong ultrasound tone-burst frequency dependence on the transfection efficiencies. Interestingly, the ultrasound signal parameters which are routinely employed in clinical therapy did not yield any statistically significant enhancement in transfection efficiency relative to their sham counterparts.

背景与目标： 发现与临床治疗中使用的低强度超声信号相似，可介导两种人前列腺癌细胞系LnCap和PC-3中的差异基因转移和绿色荧光蛋白 (GFP) 报告基因的表达。在驻波条件下，在37 ℃ 下处理存在或不存在GFP (44.5nm) 的细胞悬浮液。将细胞暴露于连续波、932.7khz超声波或几个独立的突发，每个突发包括20% 占空比 (932.7khz) 正弦波。在几个不同的实验中，突发 “重复” 频率从10Hz到10kHz不等，并且每种处理均获得净相同的超声能量暴露。通过流式细胞术监测活细胞中的瞬时GFP表达水平。研究结果表明，超声音调爆发频率对转染效率有很强的依赖性。有趣的是，与假手术相比，临床治疗中常规使用的超声信号参数在转染效率上没有任何统计学上的显着提高。

BACKGROUND & AIMS: :Different attempts were made to identify the variables that may be involved in the clinical course of cerebrovascular ischemia. In the case of stroke with mild severity (SMS), the clinical significance of neuroendocrine changes as well as of post-stroke depression (PSD) remains unknown. We therefore evaluated the presence of neuroendocrine changes in the acute and post-acute phase of SMS, and their potential role during convalescence. Serum cortisol, T4, T3, FT4, FT3, TSH and PRL levels were measured in 17 euthyroid patients with stroke on admission (day 1), following morning (day 2), 7 days and 3 months later. TSH and PRL secretion after TRH test were measured. Stroke severity on admission was determined by Scandinavian Stroke Scale (SSS). Montgomery-Asberg Depression Rating Scale (Madrs) was used for assessment of post-stroke depression. On admission, TSH and T3, were within normal limits and were greater compared to values on day 2. Lower basal TSH and decreased TSH response to TRH on day 2, were associated with stroke of greater severity. Delta-PRL after TRH on day 2 was higher in patients who develop PSD. Changes in serum thyroid hormones in SMS, reflects those of non-thyroidal illness. A mild stimulation of hypothalamic-pituitary-adrenal axis was detected. We provide evidence that PRL response to TRH, in the acute phase of stroke may be used as an index for early detection of PSD.

背景与目标： : 进行了不同的尝试来确定可能与脑血管缺血的临床过程有关的变量。对于轻度严重程度 (SMS) 的中风，神经内分泌变化以及卒中后抑郁 (PSD) 的临床意义仍然未知。因此，我们评估了SMS急性期和急性期后神经内分泌变化的存在及其在恢复期中的潜在作用。在入院时 (第1天)，第二天 (第2天)，7天和3个月后的17例甲状腺功能正常的中风患者中测量了血清皮质醇，T4，T3，FT4，FT3，TSH和PRL水平。TRH试验后测量TSH和PRL分泌。入院时卒中严重程度由斯堪的纳维亚卒中量表 (SSS) 确定。Montgomery-Asberg抑郁量表 (Madrs) 用于评估中风后抑郁。入院时，TSH和T3在正常范围内，与第2天的值相比更高。在第2天，较低的基础TSH和对TRH的TSH反应降低与严重程度更高的中风有关。发生PSD的患者在TRH后第2天的Delta-PRL较高。SMS中血清甲状腺激素的变化反映了非甲状腺疾病的变化。检测到下丘脑-垂体-肾上腺轴的轻度刺激。我们提供的证据表明，在中风急性期PRL对TRH的反应可以用作早期发现PSD的指标。

BACKGROUND & AIMS: Development of methodologies for gene transfer into the central nervous system (CNS) is important for fundamental research as well as clinical studies for gene therapy. Cationic liposomes (CL) are attractive vectors because of their safety and ease of use. However, to date only low rates of success have been reported. We succeeded in obtaining high transfection efficiencies into the newborn mouse brain in vivo by CL and a cytoplasmic gene expression system based on T7 RNA polymerase and T7 RNA polymerase- and the luciferase-gene with the T7 promoter sequence. This system showed an efficiency rate 2 orders of magnitude higher than the standard system, which used CL and luciferase genes with a Rous sarcoma virus promoter, pRSVL. In addition, in vitro experiments using LLCMK2 cells showed that cytoplasmic gene expression occurred rapidly (within 6 h) after transfection. In contrast, pRSVL required 24-48 h for induction of luciferase expression. Our results suggest that the cytoplasmic gene expression system is useful for gene delivery into the CNS.

背景与目标： 开发将基因转移到中枢神经系统 (CNS) 的方法对于基因治疗的基础研究和临床研究至关重要。阳离子脂质体 (CL) 是有吸引力的载体，因为它们的安全性和易用性。然而，迄今为止，只有低成功率的报道。我们成功地通过CL和基于T7 RNA聚合酶和T7 RNA聚合酶以及具有T7启动子序列的荧光素酶基因的细胞质基因表达系统在体内获得了高转染效率。该系统的效率比标准系统高2个数量级，标准系统使用具有Rous肉瘤病毒启动子pRSVL的CL和荧光素酶基因。此外，使用LLCMK2细胞的体外实验表明，转染后细胞质基因表达迅速 (在6小时内) 发生。相反，pRSVL需要24-48小时才能诱导荧光素酶表达。我们的结果表明，细胞质基因表达系统可用于将基因传递到CNS中。

BACKGROUND & AIMS: :Polo-like kinases (PLKs) are marked by C-terminal polo box modules with critical protein interaction and subcellular targeting roles. Slevin et al. in this issue of Structure reveal the architecture of a hidden set of polo boxes from the divergent PLK4, a critical player in centrosome duplication, shedding new light on the evolution of PLKs and their functionally related kinase ZYG-1.

背景与目标： : Polo样激酶 (plk) 由C末端polo盒模块标记，具有关键的蛋白质相互作用和亚细胞靶向作用。Slevin等人在本期《结构》中揭示了来自不同PLK4的一组隐藏的polo盒子的架构，PLK4是中心体复制的关键参与者，为plk及其功能相关激酶ZYG-1的演变提供了新的启示。

BACKGROUND & AIMS: :We reviewed six cases of primary sarcomas requiring scapulectomy within the past 13 years in the Surgery Branch of the National Cancer Institute, Bethesda, Md. Five of these patients returned for evaluation of disease status, evaluation of functional defects as determined by muscle group testing, and assessment of daily living skills and limitations. We demonstrated excellent shoulder function with partial scapulectomy and significant impairment with the additional loss of the glenoid fossa. In addition, we developed a thorough method of postoperative evaluation. Involvement of rehabilitation therapists before and after operatively is integral to this process in preparation for surgery and subsequent treatment.

背景与目标： : 在过去的13年中，我们在马里兰州贝塞斯达的国家癌症研究所外科分支机构中回顾了6例需要进行肩胛骨切除术的原发性肉瘤病例。这些患者中有五名返回以评估疾病状况，评估通过肌肉群测试确定的功能缺陷以及评估日常生活技能和局限性。我们通过部分肩胛骨切除术证明了出色的肩部功能，并通过关节盂窝的额外损失而明显受损。此外，我们开发了一种彻底的术后评估方法。在手术和后续治疗的准备过程中，康复治疗师在手术前后的参与是必不可少的。

BACKGROUND & AIMS: :Musical training has emerged as a useful framework for the investigation of training-related plasticity in the human brain. Learning to play an instrument is a highly complex task that involves the interaction of several modalities and higher-order cognitive functions and that results in behavioral, structural, and functional changes on time scales ranging from days to years. While early work focused on comparison of musical experts and novices, more recently an increasing number of controlled training studies provide clear experimental evidence for training effects. Here, we review research investigating brain plasticity induced by musical training, highlight common patterns and possible underlying mechanisms of such plasticity, and integrate these studies with findings and models for mechanisms of plasticity in other domains.

背景与目标： : 音乐训练已成为研究人脑中与训练相关的可塑性的有用框架。学习演奏乐器是一项高度复杂的任务，涉及几种模态和高阶认知功能的相互作用，并导致行为，结构和功能在从数天到数年内的时间范围内发生变化。虽然早期的工作侧重于音乐专家和新手的比较，但最近越来越多的受控训练研究为训练效果提供了明确的实验证据。在这里，我们回顾了研究由音乐训练引起的大脑可塑性的研究，强调了这种可塑性的常见模式和可能的潜在机制，并将这些研究与其他领域的可塑性机制的发现和模型相结合。

BACKGROUND & AIMS: :Flavohemoglobins (FHbs) are members of the globin superfamily, widely distributed among prokaryotes and eukaryotes that have been shown to carry out nitric oxide dioxygenase (NOD) activity. In prokaryotes, such as Escherichia coli, NOD activity is a defence mechanism against the NO release by the macrophages of the hosts' immune system during infection. Because of that, FHbs have been studied thoroughly and several drugs have been developed in an effort to fight infectious processes. Nevertheless, the protein's structural determinants involved in the NOD activity are still poorly understood. In this context, the aim of the present work is to unravel the molecular basis of FHbs structural dynamics-to-function relationship using state of the art computer simulation tools. In an effort to fulfill this goal, we studied three key processes that determine NOD activity, namely i) ligand migration into the active site ii) stabilization of the coordinated oxygen and iii) intra-protein electron transfer (ET). Our results allowed us to determine key factors related to all three processes like the presence of a long hydrophobic tunnel for ligand migration, the presence of a water mediated hydrogen bond to stabilize the coordinated oxygen and therefore achieve a high affinity, and the best possible ET paths between the FAD and the heme, where water molecules play an important role. Taken together the presented results close an important gap in our understanding of the wide and diverse globin structural-functional relationships.

背景与目标： : 黄素血红蛋白 (FHbs) 是球蛋白超家族的成员，广泛分布在原核生物和真核生物中，已证明具有一氧化氮双加氧酶 (NOD) 活性。在原核生物 (例如大肠杆菌) 中，NOD活性是抵抗宿主免疫系统巨噬细胞在感染过程中释放NO的防御机制。因此，已经对FHbs进行了彻底的研究，并开发了几种药物来对抗传染过程。尽管如此，与NOD活性有关的蛋白质的结构决定因素仍然知之甚少。在这种情况下，本工作的目的是使用最先进的计算机模拟工具来阐明FHbs结构动力学与功能关系的分子基础。为了实现这一目标，我们研究了确定NOD活性的三个关键过程，即i) 配体迁移到活性位点ii) 配位氧的稳定和iii) 蛋白质内电子转移 (ET)。我们的结果使我们能够确定与所有三个过程相关的关键因素，例如配体迁移的长疏水隧道的存在，水介导的氢键的存在以稳定配位氧并因此实现高亲和力，以及FAD和血红素之间的最佳ET路径，水分子起着重要作用。综合起来，提出的结果缩小了我们对广泛而多样的珠蛋白结构-功能关系的理解中的重要差距。

BACKGROUND & AIMS: BACKGROUND:Choline is essential for fetal brain development, and it is not known whether a typical American diet contains enough choline to ensure optimal brain development. OBJECTIVE:The study was undertaken to determine whether supplementing pregnant women with phosphatidylcholine (the main dietary source of choline) improves the cognitive abilities of their offspring. DESIGN:In a double-blind, randomized controlled trial, 140 pregnant women were randomly assigned to receive supplemental phosphatidylcholine (750 mg) or a placebo (corn oil) from 18 wk gestation through 90 d postpartum. Their infants (n = 99) were tested for short-term visuospatial memory, long-term episodic memory, language development, and global development at 10 and 12 mo of age. RESULTS:The women studied ate diets that delivered ∼360 mg choline/d in foods (∼80% of the recommended intake for pregnant women, 65% of the recommended intake for lactating women). The phosphatidylcholine supplements were well tolerated. Groups did not differ significantly in global development, language development, short-term visuospatial memory, or long-term episodic memory. CONCLUSIONS:Phosphatidylcholine supplementation of pregnant women eating diets containing moderate amounts of choline did not enhance their infants' brain function. It is possible that a longer follow-up period would reveal late-emerging effects. Moreover, future studies should determine whether supplementing mothers eating diets much lower in choline content, such as those consumed in several low-income countries, would enhance infant brain development.

背景与目标：

BACKGROUND & AIMS: :The solution of the forward problem in fluorescence molecular imaging strongly influences the successful convergence of the fluorophore reconstruction. The most common approach to meeting this problem has been to apply the diffusion approximation. However, this model is a first-order angular approximation of the radiative transfer equation, and thus is subject to some well-known limitations. This manuscript proposes a methodology that confronts these limitations by applying the radiative transfer equation in spatial regions in which the diffusion approximation gives decreased accuracy. The explicit integro differential equations that formulate this model were solved by applying the Galerkin finite element approximation. The required spatial discretization of the investigated domain was implemented through the Delaunay triangulation, while the azimuthal discretization scheme was used for the angular space. This model has been evaluated on two simulation geometries and the results were compared with results from an independent Monte Carlo method and the radiative transfer equation by calculating the absolute values of the relative errors between these models. The results show that the proposed forward solver can approximate the radiative transfer equation and the Monte Carlo method with better than 95% accuracy, while the accuracy of the diffusion approximation is approximately 10% lower.

背景与目标： : 荧光分子成像中正向问题的解决方案强烈影响荧光团重建的成功收敛。解决此问题的最常见方法是应用扩散近似。但是，该模型是辐射传递方程的一阶角近似，因此受到一些众所周知的限制。该手稿提出了一种方法，该方法通过在空间区域中应用辐射传递方程来应对这些限制，在空间区域中，扩散近似值降低了精度。通过应用Galerkin有限元近似求解了建立该模型的显式积分微分方程。通过Delaunay三角剖分实现了所研究域所需的空间离散化，而角度空间则使用了方位角离散化方案。该模型已在两个模拟几何上进行了评估，并通过计算这些模型之间相对误差的绝对值，将结果与独立的蒙特卡洛方法和辐射传递方程的结果进行了比较。结果表明，提出的前向求解器能够较好地逼近辐射传递方程和蒙特卡罗方法，精度优于95%，而扩散逼近的精度约为10%。

BACKGROUND & AIMS: :Spermatogenesis is a dynamic process that is regulated by adhesive interactions between germ and Sertoli cells. Germ cells express the Junctional Adhesion Molecule-C (JAM-C, encoded by Jam3), which localizes to germ/Sertoli cell contacts. JAM-C is involved in germ cell polarity and acrosome formation. Using a proteomic approach, we demonstrated that JAM-C interacted with the Golgi reassembly stacking protein of 55 kDa (GRASP55, encoded by Gorasp2) in developing germ cells. Generation and study of Gorasp2-/- mice revealed that knock-out mice suffered from spermatogenesis defects. Acrosome formation and polarized localization of JAM-C in spermatids were altered in Gorasp2-/- mice. In addition, Golgi morphology of spermatocytes was disturbed in Gorasp2-/- mice. Crystal structures of GRASP55 in complex with JAM-C or JAM-B revealed that GRASP55 interacted via PDZ-mediated interactions with JAMs and induced a conformational change in GRASP55 with respect of its free conformation. An in silico pharmacophore approach identified a chemical compound called Graspin that inhibited PDZ-mediated interactions of GRASP55 with JAMs. Treatment of mice with Graspin hampered the polarized localization of JAM-C in spermatids, induced the premature release of spermatids and affected the Golgi morphology of meiotic spermatocytes.

背景与目标： : 精子发生是一个动态过程，由生殖细胞和支持细胞之间的粘附相互作用调节。生殖细胞表达连接粘附分子-C (JAM-C，由Jam3编码)，其定位于生殖/支持细胞接触。JAM-C参与生殖细胞极性和胚体形成。使用蛋白质组学方法，我们证明了JAM-C在发育中的生殖细胞中与55 kDa的高尔基重组堆积蛋白 (GRASP55，由Gorasp2编码) 相互作用。Gorasp2-/-小鼠的产生和研究表明，敲除小鼠患有精子发生缺陷。在Gorasp2-/-小鼠中，精子细胞中JAM-C的顶体形成和极化定位发生了改变。此外，Gorasp2-/-小鼠的精母细胞高尔基体形态受到干扰。GRASP55与JAM-C或JAM-B配合物的晶体结构表明，GRASP55通过PDZ介导的与JAMs的相互作用，并在其自由构象方面引起GRASP55的构象变化。计算机药效团方法确定了一种称为Graspin的化合物，该化合物抑制了PDZ介导的GRASP55与果酱的相互作用。用Graspin处理小鼠会阻碍JAM-C在精子中的极化定位，诱导精子的过早释放并影响减数分裂精母细胞的高尔基体形态。