BACKGROUND & AIMS: :A new optimization model of molecular docking is proposed, and a fast flexible docking method based on an improved adaptive genetic algorithm is developed in this paper. The algorithm takes some advanced techniques, such as multi-population genetic strategy, entropy-based searching technique with self-adaptation and the quasi-exact penalty. A new iteration scheme in conjunction with above techniques is employed to speed up the optimization process and to ensure very rapid and steady convergence. The docking accuracy and efficiency of the method are evaluated by docking results from GOLD test data set, which contains 134 protein-ligand complexes. In over 66.2% of the complexes, the docked pose was within 2.0 A root-mean-square deviation (RMSD) of the X-ray structure. Docking time is approximately in proportion to the number of the rotatable bonds of ligands.

背景与目标： 提出了一种新的分子对接优化模型，提出了一种基于改进的自适应遗传算法的快速柔性对接方法。该算法采用了一些先进的技术，例如多种群遗传策略，具有自适应的基于熵的搜索技术和准精确惩罚。结合上述技术，采用了新的迭代方案来加快优化过程并确保非常快速和稳定的收敛。通过来自包含134蛋白质-配体复合物的GOLD测试数据集的对接结果来评估该方法的对接精度和效率。在超过66.2% 的复合体中，对接的姿势在x射线结构的均方根偏差 (RMSD) 2.0内。对接时间与配体的可旋转键的数量大致成比例。

BACKGROUND & AIMS: :Obesity and associated metabolic diseases have become a priority area of study due to the exponential increase in their prevalence and the corresponding health and economic impact. In the last decade, brown adipose tissue has become an attractive target to treat obesity. However, environmental variables such as temperature and the dynamics of energy expenditure could influence brown adipose tissue activity. Currently, most metabolic studies are carried out at a room temperature of 21 °C, which is considered a thermoneutral zone for adult humans. However, in mice this chronic cold temperature triggers an increase in their adaptive thermogenesis. In this review, we aim to cover important aspects related to the adaptation of animals to room temperature, the influence of housing and temperature on the development of metabolic phenotypes in experimental mice and their translation to human physiology. Mice studies performed in chronic cold or thermoneutral conditions allow us to better understand underlying physiological mechanisms for successful, reproducible translation into humans in the fight against obesity and metabolic diseases.

背景与目标： : 肥胖和相关的代谢疾病已成为研究的优先领域，因为它们的患病率呈指数级增长以及相应的健康和经济影响。在过去的十年中，棕色脂肪组织已成为治疗肥胖症的诱人靶标。然而，环境变量 (例如温度和能量消耗的动态变化) 可能会影响棕色脂肪组织的活性。目前，大多数代谢研究都是在21 °C的室温下进行的，这被认为是成年人的热中性区域。然而，在小鼠中，这种慢性低温会触发其适应性产热的增加。在这篇综述中，我们旨在涵盖与动物适应室温，住房和温度对实验小鼠代谢表型发展的影响及其转化为人类生理学有关的重要方面。在慢性感冒或热中性条件下进行的小鼠研究使我们能够更好地了解潜在的生理机制，从而成功地，可重复地转化为人类，以对抗肥胖和代谢疾病。

BACKGROUND & AIMS: :The purpose of this study was to determine the extent to which hindlimb muscles of mdx mice adapt to a voluntary endurance type of exercise. mdx and C57BL mice engaged in 8 weeks of wheel running or maintained normal cage activities. Beneficial adaptations that occurred in mdx mice included changes in muscle mass, fiber size, and fiber types based on myosin heavy chain (MHC) isoform expression. These adaptations occurred without increases in fiber central nuclei and embryonic MHC expression. An undesirable outcome, however, was that muscle mitochondrial enzyme activities did not improve with exercise in mdx mice as they did in C57BL mice. Cellular remodeling of dystrophic muscle following exercise has not been studied adequately. In this study we found that some, but not all, of the expected adaptations occurred in mdx mouse muscle. We must better understand these (non)adaptations in order to inform individuals with DMD about the benefits of exercise.

背景与目标： : 这项研究的目的是确定mdx小鼠的后肢肌肉对自愿耐力运动的适应程度。mdx和C57BL小鼠参加了8周的轮跑或保持了正常的笼活动。在mdx小鼠中发生的有益适应包括基于肌球蛋白重链 (MHC) 亚型表达的肌肉质量，纤维大小和纤维类型的变化。这些适应发生时，纤维中央核和胚胎MHC表达没有增加。然而，一个不良的结果是，在mdx小鼠中，肌肉线粒体酶活性没有像在C57BL小鼠中那样在运动中改善。运动后营养不良肌肉的细胞重塑尚未得到充分研究。在这项研究中，我们发现mdx小鼠肌肉中发生了一些但不是全部的预期适应性。我们必须更好地理解这些 (非) 适应，以便告知DMD患者锻炼的好处。

BACKGROUND & AIMS: :Coxiella burnetii is an obligate intracellular bacterial pathogen that causes the zoonosis Q fever. While an effective whole-cell vaccine (WCV) against Q fever exists, the vaccine has limitations in being highly reactogenic in sensitized individuals. Thus, a safe and effective vaccine based on recombinant protein antigen (Ag) is desirable. To achieve this goal, a better understanding of the host response to primary infection and the precise mechanisms involved in protective immunity to C. burnetii are needed. This review summarizes our current understanding of adaptive immunity to C. burnetii with a focus on recent developments in the field.

背景与目标： : 柯氏菌是一种专性细胞内细菌病原体，可引起人畜共患病Q发热。尽管存在针对Q发热的有效全细胞疫苗 (WCV)，但该疫苗在致敏个体中具有高反应性的局限性。因此，基于重组蛋白抗原 (Ag) 的安全有效的疫苗是理想的。为了实现这一目标，需要更好地了解宿主对原发性感染的反应以及对burnetii的保护性免疫所涉及的确切机制。这篇综述总结了我们目前对C. burnetii适应性免疫的理解，重点是该领域的最新发展。

BACKGROUND & AIMS: OBJECTIVE:To develop outpatient Adaptive Short Forms for the Activity Measure for Post-Acute Care item bank for use in outpatient therapy settings. DESIGN:A convenience sample of 11,809 adults with spine, lower limb, upper limb, and miscellaneous orthopedic impairments who received outpatient rehabilitation in 1 of 127 outpatient rehabilitation clinics in the United States. We identified optimal items for use in developing outpatient Adaptive Short Forms based on the Basic Mobility and Daily Activities domains of the Activity Measure for Post-Acute Care item bank. Patient scores were derived from the Activity Measure for Post-Acute Care computerized adaptive testing program. Items were selected for inclusion on the Adaptive Short Forms based on functional content, range of item coverage, measurement precision, item exposure rate, and data collection burden. RESULTS:Two outpatient Adaptive Short Forms were developed: (1) an 18-item Basic Mobility Adaptive Short Form and (2) a 15-item Daily Activities Adaptive Short Form, derived from the same item bank used to develop the Activity Measure for Post-Acute Care computerized adaptive testing program. Both Adaptive Short Forms achieved acceptable psychometric properties. CONCLUSIONS:In outpatient postacute care settings where computerized adaptive testing outcome applications are currently not feasible, item response theory-derived Adaptive Short Forms provide the efficient capability to monitor patients' functional outcomes. The development of Adaptive Short Form functional outcome instruments linked by a common, calibrated item bank has the potential to create a bridge to outcome monitoring across postacute care settings and can facilitate the eventual transformation from Adaptive Short Forms to computerized adaptive testing applications easier and more acceptable to the rehabilitation community.

背景与目标：

BACKGROUND & AIMS: :This paper proposes a novel prewhitening eigenspace beamformer suitable for magnetoencephalogram (MEG) source reconstruction when large background brain activities exist. The prerequisite for the method is that control-state measurements, which contain only the contributions from the background interference, be available, and that the covariance matrix of the background interference can be obtained from such control-state measurements. The proposed method then uses this interference covariance matrix to remove the influence of the interference in the reconstruction obtained from the target measurements. A numerical example, as well as applications to two types of MEG data, demonstrates the effectiveness of the proposed method.

背景与目标： : 本文提出了一种新型的预白化特征空间波束形成器，适用于存在大背景脑活动时的脑磁图 (MEG) 源重建。该方法的先决条件是仅包含来自背景干扰的贡献的控制状态测量是可用的，并且可以从这种控制状态测量中获得背景干扰的协方差矩阵。然后，所提出的方法使用此干扰协方差矩阵来消除从目标测量获得的重建中的干扰的影响。一个数值示例以及在两种类型的MEG数据中的应用证明了该方法的有效性。

BACKGROUND & AIMS: :Hybridization is increasingly recognized as an important force impacting adaptation and evolution in many lineages of fungi. During hybridization, divergent genomes and alleles are brought together into the same cell, potentiating adaptation by increasing genomic plasticity. Here, we review hybridization in fungi by focusing on two fungal pathogens of animals. Hybridization is common between the basidiomycete yeast species Cryptococcusneoformans × Cryptococcusdeneoformans, and hybrid genotypes are frequently found in both environmental and clinical settings. The two species show 10-15% nucleotide divergence at the genome level, and their hybrids are highly heterozygous. Though largely sterile and unable to mate, these hybrids can propagate asexually and generate diverse genotypes by nondisjunction, aberrant meiosis, mitotic recombination, and gene conversion. Under stress conditions, the rate of such genetic changes can increase, leading to rapid adaptation. Conversely, in hybrids formed between lineages of the chytridiomycete frog pathogen Batrachochytriumdendrobatidis (Bd), the parental genotypes are considerably less diverged (0.2% divergent). Bd hybrids are formed from crosses between lineages that rarely undergo sex. A common theme in both species is that hybrids show genome plasticity via aneuploidy or loss of heterozygosity and leverage these mechanisms as a rapid way to generate genotypic/phenotypic diversity. Some hybrids show greater fitness and survival in both virulence and virulence-associated phenotypes than parental lineages under certain conditions. These studies showcase how experimentation in model species such as Cryptococcus can be a powerful tool in elucidating the genotypic and phenotypic consequences of hybridization.

背景与目标： : 杂交越来越被认为是影响许多真菌谱系适应和进化的重要力量。在杂交过程中，不同的基因组和等位基因被聚集到同一细胞中，通过增加基因组可塑性来增强适应性。在这里，我们通过关注动物的两种真菌病原体来回顾真菌中的杂交。担子菌酵母物种隐球菌 × 隐球菌之间的杂交很常见，并且在环境和临床环境中经常发现杂交基因型。这两个物种在基因组水平上显示出10-15% 个核苷酸的差异，并且它们的杂种是高度杂合的。尽管这些杂种大部分不育且无法交配，但它们可以无性繁殖，并通过不分离，异常减数分裂，有丝分裂重组和基因转化产生不同的基因型。在压力条件下，这种遗传变化的速度会增加，从而导致快速适应。相反，在凝乳酵母蛙病原体Batrachochytriumdendrobatidis (Bd) 的谱系之间形成的杂种中，亲本基因型的差异要小得多 (0.2% 差异)。Bd杂种是由很少发生性行为的谱系之间的杂交形成的。这两个物种的共同主题是，杂种通过非整倍体或杂合性丧失显示基因组可塑性，并利用这些机制作为产生基因型/表型多样性的快速方法。在某些条件下，某些杂种在毒力和毒力相关表型上都比亲本谱系显示出更高的适应性和存活率。这些研究展示了在模型物种 (如隐球菌) 中的实验如何成为阐明杂交的基因型和表型后果的有力工具。

BACKGROUND & AIMS: :Adaptive radiation plays a fundamental role in our understanding of the evolutionary process. However, the concept has provoked strong and differing opinions concerning its definition and nature among researchers studying a wide diversity of systems. Here, we take a broad view of what constitutes an adaptive radiation, and seek to find commonalities among disparate examples, ranging from plants to invertebrate and vertebrate animals, and remote islands to lakes and continents, to better understand processes shared across adaptive radiations. We surveyed many groups to evaluate factors considered important in a large variety of species radiations. In each of these studies, ecological opportunity of some form is identified as a prerequisite for adaptive radiation. However, evolvability, which can be enhanced by hybridization between distantly related species, may play a role in seeding entire radiations. Within radiations, the processes that lead to speciation depend largely on (1) whether the primary drivers of ecological shifts are (a) external to the membership of the radiation itself (mostly divergent or disruptive ecological selection) or (b) due to competition within the radiation membership (interactions among members) subsequent to reproductive isolation in similar environments, and (2) the extent and timing of admixture. These differences translate into different patterns of species accumulation and subsequent patterns of diversity across an adaptive radiation. Adaptive radiations occur in an extraordinary diversity of different ways, and continue to provide rich data for a better understanding of the diversification of life.

背景与目标： : 适应性辐射在我们对进化过程的理解中起着至关重要的作用。但是，在研究广泛的系统多样性的研究人员中，该概念在其定义和性质方面引起了强烈而不同的意见。在这里，我们从广义上了解什么是适应性辐射，并寻求在不同的例子中找到共同点，从植物到无脊椎动物和脊椎动物，从偏远岛屿到湖泊和大陆，以更好地理解适应性辐射共享的过程。我们对许多小组进行了调查，以评估被认为在多种物种辐射中重要的因素。在这些研究中的每一项中，都将某种形式的生态机会确定为适应性辐射的先决条件。但是，可以通过远缘物种之间的杂交来增强进化能力，可能在播种整个辐射中起作用。在辐射范围内，导致物种形成的过程在很大程度上取决于 (1) 生态变化的主要驱动因素是 (a) 辐射本身的成员资格 (主要是发散的或破坏性的生态选择) 还是 (b) 由于辐射成员资格内的竞争 (成员之间的相互作用) 类似的环境，(2) 混合的程度和时间。这些差异转化为不同的物种积累模式以及随后的适应性辐射多样性模式。自适应辐射以不同方式的非凡多样性发生，并继续提供丰富的数据，以更好地了解生活的多样化。

BACKGROUND & AIMS: :The interplay between space and evolution is an important issue in population dynamics, that is particularly crucial in the emergence of polymorphism and spatial patterns. Recently, biological studies suggest that invasion and evolution are closely related. Here, we model the interplay between space and evolution starting with an individual-based approach and show the important role of parameter scalings on clustering and invasion. We consider a stochastic discrete model with birth, death, competition, mutation and spatial diffusion, where all the parameters may depend both on the position and on the phenotypic trait of individuals. The spatial motion is driven by a reflected diffusion in a bounded domain. The interaction is modelled as a trait competition between individuals within a given spatial interaction range. First, we give an algorithmic construction of the process. Next, we obtain large population approximations, as weak solutions of nonlinear reaction-diffusion equations. As the spatial interaction range is fixed, the nonlinearity is nonlocal. Then, we make the interaction range decrease to zero and prove the convergence to spatially localized nonlinear reaction-diffusion equations. Finally, a discussion of three concrete examples is proposed, based on simulations of the microscopic individual-based model. These examples illustrate the strong effects of the spatial interaction range on the emergence of spatial and phenotypic diversity (clustering and polymorphism) and on the interplay between invasion and evolution. The simulations focus on the qualitative differences between local and nonlocal interactions.

背景与目标： : 空间与进化之间的相互作用是人口动态中的一个重要问题，这对于多态性和空间格局的出现尤为重要。最近，生物学研究表明入侵和进化密切相关。在这里，我们从基于个体的方法开始对空间与进化之间的相互作用进行建模，并显示了参数缩放在聚类和入侵中的重要作用。我们考虑具有出生，死亡，竞争，突变和空间扩散的随机离散模型，其中所有参数都可能取决于个体的位置和表型特征。空间运动由有界域中的反射扩散驱动。交互被建模为给定空间交互范围内个体之间的特质竞争。首先，我们给出了该过程的算法构造。接下来，我们获得大量的人口近似值，作为非线性反应扩散方程的弱解。由于空间相互作用范围固定，因此非线性是非局部的。然后，我们使相互作用范围减小到零，并证明了对空间局部化非线性反应扩散方程的收敛性。最后，基于微观个体模型的模拟，提出了三个具体实例的讨论。这些示例说明了空间相互作用范围对空间和表型多样性 (聚类和多态性) 的出现以及入侵与进化之间的相互作用的强烈影响。模拟的重点是局部和非局部相互作用之间的质量差异。

BACKGROUND & AIMS: :The statistical principles of fully adaptive designs are outlined. The options of flexibility and the price to be paid in terms of statistical properties of the test procedures are discussed. It is stressed that controlled inference after major design modifications (changing hypotheses) will include a penalty: Intersections among all the hypotheses considered throughout the trial have to be rejected before testing individual hypotheses. Moreover, feasibility in terms of integrity and persuasiveness of the results achieved after adaptations based on unblinded data is considered as the crucial issue in practice. In the second part, sample size adaptive procedures are considered testing a large number of hypotheses under constraints on total sample size as in genetic studies. The advantage of sequential procedures is sketched for the example of two-stage designs with a pilot phase for screening promising hypotheses (markers) and controlling the false discovery rate. Finally, we turn to the clinical problem how to select markers and estimate a score from limited samples, e.g. for predicting the response to therapy of a future patient. The predictive ability of such scores will be rather poor when investigating a large number of hypotheses and truly large marker effects are lacking. An obvious dilemma will show up: More optimistic selection rules may be superior if in fact effective markers exist, but will produce more nuisance prediction if no effective markers exist compared with more cautious strategies, e.g. aiming at some control of type I error probabilities.

背景与目标： : 概述了完全自适应设计的统计原理。根据测试程序的统计特性，讨论了灵活性的选择和要支付的价格。需要强调的是，重大设计修改 (改变假设) 后的受控推理将包括一个惩罚: 在测试单个假设之前，必须拒绝整个试验中考虑的所有假设之间的交叉。此外，根据非盲数据进行改编后，在完整性和说服力方面的可行性被认为是实践中的关键问题。在第二部分中，考虑了样本量自适应程序，例如在遗传研究中，在总样本量的约束下测试了大量假设。对于两阶段设计的示例，概述了顺序程序的优势，该阶段具有试点阶段，用于筛选有希望的假设 (标记) 并控制错误发现率。最后，我们转向临床问题如何从有限的样本中选择标记并估计分数，例如用于预测未来患者对治疗的反应。在调查大量假设时，此类分数的预测能力将很差，并且缺乏真正的大标记效应。一个明显的困境将出现: 如果实际上存在有效的标记，则更乐观的选择规则可能会更优越，但是如果与更谨慎的策略相比，没有有效的标记存在，则会产生更多的干扰预测，例如针对I型错误概率的某些控制。

BACKGROUND & AIMS: :Susceptibility to mycobacterial infection has long been associated with defects in T cell immunity, such as those conferred by HIV infection or iatrogenic immune suppression. However, despite these well-recognized predispositions to clinical disease with tuberculosis and nontuberculous mycobacteria, the genetic disorders that are relatively specific for mycobacterial infection with nontuberculous bacteria and bacille Calmette Guerin (BCG) involve the innate immune pathways, and all engage interferon gamma and IL-12 production, signaling, and availability.

背景与目标： : 长期以来，分枝杆菌感染的易感性与T细胞免疫缺陷有关，例如HIV感染或医源性免疫抑制引起的缺陷。然而，尽管这些公认的结核病和非结核分枝杆菌的临床疾病易感性，但非结核细菌和卡介苗 (BCG) 的分枝杆菌感染相对特异性的遗传疾病涉及先天免疫途径，并且都涉及干扰素 γ 和IL-12的产生，信号传导和可用性。

BACKGROUND & AIMS: BACKGROUND:There is widespread concern across the clinical and research communities that clinical trials, powered for patient-reported outcomes, testing new surgical procedures are often expensive and time-consuming, particularly when the new intervention is shown to be no better than the standard. Conventional (non-adaptive) randomised controlled trials (RCTs) are perceived as being particularly inefficient in this setting. Therefore, we have developed an adaptive group sequential design that allows early endpoints to inform decision making and show, through simulations and a worked example, that these designs are feasible and often preferable to conventional non-adaptive designs. The methodology is motivated by an ongoing clinical trial investigating a saline-filled balloon, inserted above the main joint of the shoulder at the end of arthroscopic debridement, for treatment of tears of rotor cuff tendons. This research question and setting is typical of many studies undertaken to assess new surgical procedures. METHODS:Test statistics are presented based on the setting of two early outcomes, and methods for estimation of sequential stopping boundaries are described. A framework for the implementation of simulations to evaluate design characteristics is also described. RESULTS:Simulations show that designs with one, two and three early looks are feasible and, with appropriately chosen futility stopping boundaries, have appealing design characteristics. A number of possible design options are described that have good power and a high probability of stopping for futility if there is no evidence of a treatment effect at early looks. A worked example, with code in R, provides a practical demonstration of how the design might work in a real study. CONCLUSIONS:In summary, we show that adaptive designs are feasible and could work in practice. We describe the operating characteristics of the designs and provide guidelines for appropriate values for the stopping boundaries for the START:REACTS (Sub-acromial spacer for Tears Affecting Rotator cuff Tendons: a Randomised, Efficient, Adaptive Clinical Trial in Surgery) study. TRIAL REGISTRATION:ISRCTN Registry, ISRCTN17825590. Registered on 5 March 2018.

背景与目标：

BACKGROUND & AIMS: :In this study, synthetic vaccine nanoparticles (SVNPs) that efficiently targeted lymph nodes, where immune responses against foreign antigens are primed, were developed to enhance antitumor immunity. The size (20-70 nm) and surface character (amination) of poly(γ-glutamic acid)-based SVNPs were selected for effective loading and delivery (i.e., migration and retention) of model tumor antigen (OVA) and toll-like receptor 3 agonist (poly (I:C)) to immune cells in lymph nodes. Antigen-presenting cells treated with SVNP-OVA and SVNP-IC showed higher uptake of OVA and poly (I:C) and higher secretion of inflammatory cytokines (TNF-α, IL-6) and type I interferon (IFN-α, IFN-β) than those treated with OVA and poly (I:C) alone. In vivo analysis revealed higher levels of activation markers, inflammatory cytokines, and type I IFNs in the lymph nodes of mice immunized with SVNP-IC compared to those of mice in other groups. SVNP-IC-treated mice showed significantly greater in vivo natural killer cell expansion/activation (NK1.1+ cells) and CD8+ T cell response (CD8+ INF-γ+ cells) in innate and adaptive immunity, respectively. Both preventive and therapeutic vaccination of EG7-OVA tumor-bearing mice using the simultaneous injection of both SVNP-OVA and SVNP-IC induced higher antitumor immunity and inhibited tumor growth.

背景与目标： : 在这项研究中，开发了有效靶向淋巴结的合成疫苗纳米颗粒 (svnp)，以增强抗肿瘤免疫力，在淋巴结中引发针对外来抗原的免疫反应。选择基于聚 (γ-谷氨酸) 的svnp的尺寸 (20-70 nm) 和表面特性 (胺化)，以有效加载和递送 (即，模型肿瘤抗原 (OVA) 和toll样受体3激动剂 (poly (I:C)) 向淋巴结免疫细胞的迁移和保留。用SVNP-OVA和SVNP-IC处理的抗原呈递细胞显示出更高的OVA和poly (I:C) 摄取和更高的炎性细胞因子 (TNF-α，IL-6) 和I型干扰素 (IFN-α，IFN-β) 比单独用OVA和poly (I:C) 处理的那些。体内分析显示，与其他组的小鼠相比，用svnp-ic免疫的小鼠淋巴结中的活化标志物，炎性细胞因子和I型ifn水平更高。SVNP-IC处理的小鼠在固有免疫和适应性免疫中分别显示出明显更大的体内自然杀伤细胞扩增/活化 (NK1.1细胞) 和CD8 T细胞反应 (CD8 INF-γ 细胞)。同时注射svnp-ova和svnp-ic对EG7-OVA荷瘤小鼠进行预防和治疗性疫苗接种均诱导更高的抗肿瘤免疫并抑制肿瘤生长。

BACKGROUND & AIMS: :The diversity and activity of leukocytes is controlled by genetic and environmental influences to maintain balanced immune responses. However, the relative contribution of environmental compared with genetic factors that affect variations in immune traits is unknown. Here we analyse 23,394 immune phenotypes in 497 adult female twins. 76% of these traits show a predominantly heritable influence, whereas 24% are mostly influenced by environment. These data highlight the importance of shared childhood environmental influences such as diet, infections or microbes in shaping immune homeostasis for monocytes, B1 cells, γδ T cells and NKT cells, whereas dendritic cells, B2 cells, CD4+ T and CD8+ T cells are more influenced by genetics. Although leukocyte subsets are influenced by genetics and environment, adaptive immune traits are more affected by genetics, whereas innate immune traits are more affected by environment.

背景与目标： : 白细胞的多样性和活性受遗传和环境影响控制，以维持平衡的免疫反应。然而，与影响免疫性状变异的遗传因素相比，环境的相对贡献尚不清楚。在这里，我们分析了497成年女性双胞胎的23,394免疫表型。这些特征中的76% 都显示出主要的可遗传影响，而24% 主要受环境影响。这些数据强调了共同的儿童环境影响 (例如饮食，感染或微生物) 在塑造单核细胞，B1细胞，γ δ T细胞和NKT细胞的免疫稳态方面的重要性，而树突状细胞，B2细胞，CD4 T和CD8 T细胞更受遗传学影响。尽管白细胞亚群受遗传和环境的影响，但适应性免疫性状受遗传的影响更大，而先天免疫性状受环境的影响更大。

BACKGROUND & AIMS: :The C (-1019) G rs6295 promoter polymorphism of the serotonin-1A (5-HT1A) receptor gene is associated with major depression in several but not all studies, suggesting that compensatory mechanisms mediate resilience. The rs6295 risk allele prevents binding of the repressor Deaf1 increasing 5-HT1A receptor gene transcription, and the Deaf1-/- mouse model shows an increase in 5-HT1A autoreceptor expression. In this study, Deaf1-/- mice bred on a mixed C57BL6-BALB/c background were compared to wild-type littermates for 5-HT1A autoreceptor function and behavior in males and females. Despite a sustained increase in 5-HT1A autoreceptor binding levels, the amplitude of the 5-HT1A autoreceptor-mediated current in 5-HT neurons was unaltered in Deaf1-/- mice, suggesting compensatory changes in receptor function. Consistent with increased 5-HT1A autoreceptor function in vivo, hypothermia induced by the 5-HT1A agonist DPAT was augmented in early generation male but not female Deaf1-/- mice, but was reduced with succeeding generations. Loss of Deaf1 resulted in a mild anxiety phenotype that was sex-and test-dependent, with no change in depression-like behavior. Male Deaf1 knockout mice displayed anxiety-like behavior in the open field and light-dark tests, while female Deaf1-/- mice showed increased anxiety only in the elevated plus maze. These data show that altered 5-HT1A autoreceptor regulation in male Deaf1-/- mice can be compensated for by generational adaptation of receptor response that may help to normalize behavior. The sex dependence of Deaf1 function in mice is consistent with a greater role for 5-HT1A autoreceptors in sensitivity to depression in men.

背景与目标： : 在一些但不是所有研究中，serotonin-1A (5-HT1A) 受体基因的C (-1019) G rs6295启动子多态性与严重抑郁症有关，表明代偿机制介导了复原力。rs6295风险等位基因阻止阻遏物Deaf1的结合增加5-HT1A受体基因的转录，并且Deaf1-/-小鼠模型显示5-HT1A自身受体表达增加。在这项研究中，将在混合C57BL6-BALB/c背景下繁殖的Deaf1-/-小鼠与野生型同窝小鼠进行了5-HT1A自身受体功能和雄性和雌性行为的比较。尽管5-HT1A自身受体结合水平持续增加，但在Deaf1-/-小鼠中5-HT1A自身受体介导的5-HT神经元电流的幅度并未改变，表明受体功能发生了代偿性变化。与体内5-HT1A自身受体功能增加一致，由5-HT1A激动剂DPAT诱导的体温过低在早期雄性但雌性Deaf1-/-小鼠中增加，但在后代中减少。Deaf1的缺失导致轻度焦虑表型，该表型依赖于性别和测试，而抑郁样行为没有变化。雄性Deaf1基因敲除小鼠在野外和明暗测试中表现出类似焦虑的行为，而雌性Deaf1-/-小鼠仅在高架迷宫中表现出焦虑增加。这些数据表明，雄性Deaf1-/-小鼠中5-HT1A自身受体调节的改变可以通过受体反应的世代适应来补偿，这可能有助于使行为正常化。小鼠中Deaf1功能的性别依赖性与5-HT1A自身受体在男性对抑郁症敏感性中的更大作用一致。