• 【当存在较大背景脑活动时,一种用于MEG源重建的新型自适应波束形成器有效。】 复制标题 收藏 收藏
    DOI:10.1109/TBME.2006.878119 复制DOI
    作者列表:Sekihara K,Hild KE 2nd,Nagarajan SS
    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。
  • 【杂交促进了两种主要真菌病原体的适应性进化。】 复制标题 收藏 收藏
    DOI:10.3390/genes11010101 复制DOI
    作者列表:Samarasinghe H,You M,Jenkinson TS,Xu J,James TY
    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。
  • 【比较跨空间,时间和分类单元的自适应辐射。】 复制标题 收藏 收藏
    DOI:10.1093/jhered/esz064 复制DOI
    作者列表:
    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。
  • 【基于个体的空间结构种群的入侵和适应性进化。】 复制标题 收藏 收藏
    DOI:10.1007/s00285-007-0072-z 复制DOI
    作者列表:Champagnat N,Méléard S
    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。
  • 【适应性设计: 在大海捞针-医学研究中的新挑战。】 复制标题 收藏 收藏
    DOI:10.1002/sim.3090 复制DOI
    作者列表:Bauer P
    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。
  • 【干扰素 γ,IL-12,IL-12R和STAT-1免疫缺陷病: 先天免疫和适应性免疫界面的障碍。】 复制标题 收藏 收藏
    DOI:10.1007/s12026-007-0045-8 复制DOI
    作者列表:Holland SM
    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。
  • 【一项使用早期终点为决策提供信息的适应性两臂临床试验: 肩峰下间隔物修复肩袖肌腱撕裂的研究设计。】 复制标题 收藏 收藏
    DOI:10.1186/s13063-019-3708-6 复制DOI
    作者列表:Parsons N,Stallard N,Parsons H,Wells P,Underwood M,Mason J,Metcalfe A
    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:
  • 【合成疫苗纳米颗粒靶向淋巴结触发增强的先天和适应性抗肿瘤免疫。】 复制标题 收藏 收藏
    DOI:10.1016/j.biomaterials.2017.03.034 复制DOI
    作者列表:Kim SY,Noh YW,Kang TH,Kim JE,Kim S,Um SH,Oh DB,Park YM,Lim YT
    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。
  • 【先天免疫性状和适应性免疫性状受遗传和环境因素的差异影响。】 复制标题 收藏 收藏
    DOI:10.1038/ncomms13850 复制DOI
    作者列表:Mangino M,Roederer M,Beddall MH,Nestle FO,Spector TD
    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。
  • 【Deaf1-deficient小鼠serotonin-1A自受体功能和焦虑的性别依赖性适应性变化。】 复制标题 收藏 收藏
    DOI:10.1186/s13041-016-0254-y 复制DOI
    作者列表:Luckhart C,Philippe TJ,Le François B,Vahid-Ansari F,Geddes SD,Béïque JC,Lagace DC,Daigle M,Albert PR
    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。
  • 【缺氧诱导因子1α 促进慢性脑低灌注大鼠模型的内源性适应性反应。】 复制标题 收藏 收藏
    DOI:10.3390/ijms18010003 复制DOI
    作者列表:Yang Y,Ju J,Deng M,Wang J,Liu H,Xiong L,Zhang J
    BACKGROUND & AIMS: :Hypoxia inducible factor 1α (HIF-1α), a pivotal regulator of gene expression in response to hypoxia and ischemia, is now considered to regulate both pro-survival and pro-death responses depending on the duration and severity of the stress. We previously showed that chronic global cerebral hypoperfusion (CCH) triggered long-lasting accumulation of HIF-1α protein in the hippocampus of rats. However, the role of the stabilized HIF-1α in CCH is obscure. Here, we knock down endogenous HIF-1α to determine whether and how HIF-1α affects the disease processes and phenotypes of CCH. Lentivirus expressing HIF-1α small hairpin RNA was injected into the bilateral hippocampus and bilateral ventricles to knock down HIF-1α gene expression in the hippocampus and other brain areas. Permanent bilateral common carotid artery occlusions, known as 2-vessel occlusions (2VOs), were used to induce CCH in rats. Angiogenesis, oxidative stress, histopathological changes of the brain, and cognitive function were tested. Knockdown of HIF-1α prior to 2VO significantly exacerbates the impairment of learning and memory after four weeks of CCH. Mechanically, reduced cerebral angiogenesis, increased oxidative damage, and increased density of astrocytes and microglia in the cortex and some subregions of hippocampus are also shown after four weeks of CCH. Furthermore, HIF-1α knockdown also disrupts upregulation of regulated downstream genes. Our findings suggest that HIF-1α-protects the brain from oxidative stress and inflammation response in the disease process of CCH. Accumulated HIF-1α during CCH mediates endogenous adaptive processes to defend against more severe hypoperfusion injury of the brain, which may provide a therapeutic benefit.
    背景与目标: : 缺氧诱导因子1α (HIF-1α) 是响应缺氧和缺血的基因表达的关键调节剂,现在被认为可以根据压力的持续时间和严重程度来调节促生存和促死亡反应。我们先前显示,慢性全脑低灌注 (CCH) 触发了大鼠海马中HIF-1α 蛋白的长期积累。然而,稳定的HIF-1α 在CCH中的作用尚不清楚。在这里,我们敲除内源性HIF-1α,以确定HIF-1α 是否以及如何影响CCH的疾病过程和表型。将表达HIF-1α 小发夹RNA的慢病毒注入双侧海马和双侧脑室,以降低海马和其他脑区的HIF-1α 基因表达。永久性双侧颈总动脉闭塞,称为2血管闭塞 (2VOs),用于诱导大鼠CCH。测试了血管生成,氧化应激,大脑的组织病理学变化和认知功能。在2VO之前敲低HIF-1α 会显着加剧CCH四周后学习和记忆的障碍。在机械上,CCH四周后,还显示出脑血管生成减少,氧化损伤增加以及皮质和海马某些亚区域中星形胶质细胞和小胶质细胞密度增加。此外,HIF-1α 敲低还会破坏受调控的下游基因的上调。我们的发现表明,在CCH的疾病过程中,hif-1α-可以保护大脑免受氧化应激和炎症反应的影响。CCH期间累积的HIF-1α 介导内源性适应性过程,以防御更严重的脑低灌注损伤,这可能提供治疗益处。
  • 【流行病作为决定寿命设定点的自适应驱动力。】 复制标题 收藏 收藏
    DOI:10.1073/pnas.1920988117 复制DOI
    作者列表:Lidsky PV,Andino R
    BACKGROUND & AIMS: :Species-specific limits to lifespan (lifespan setpoint) determine the life expectancy of any given organism. Whether limiting lifespan provides an evolutionary benefit or is the result of an inevitable decline in fitness remains controversial. The identification of mutations extending lifespan suggests that aging is under genetic control, but the evolutionary driving forces limiting lifespan have not been defined. By examining the impact of lifespan on pathogen spread in a population, we propose that epidemics drive lifespan setpoints' evolution. Shorter lifespan limits infection spread and accelerates pathogen clearance when compared to populations with longer-lived individuals. Limiting longevity is particularly beneficial in the context of zoonotic transmissions, where pathogens must undergo adaptation to a new host. Strikingly, in populations exposed to pathogens, shorter-living variants outcompete individuals with longer lifespans. We submit that infection outbreaks can contribute to control the evolution of species' lifespan setpoints.
    背景与目标: : 物种特定的寿命限制 (寿命设定点) 决定了任何给定生物的预期寿命。限制寿命是否会带来进化上的好处,还是不可避免的适应性下降的结果,仍存在争议。对延长寿命的突变的鉴定表明,衰老处于遗传控制之下,但是尚未定义限制寿命的进化驱动力。通过研究寿命对人群中病原体传播的影响,我们建议流行病推动寿命设定点的演变。与寿命较长的个体相比,较短的寿命限制了感染的传播并加速了病原体的清除。在人畜共患病传播的情况下,限制寿命特别有益,在这种情况下,病原体必须适应新的宿主。令人惊讶的是,在暴露于病原体的人群中,寿命较短的变异体胜过寿命较长的个体。我们认为,感染暴发有助于控制物种寿命设定点的演变。
  • 【MR-linac工作流中适应性前列腺癌放射治疗的剂量学效应。】 复制标题 收藏 收藏
    DOI:10.1186/s13014-020-01604-5 复制DOI
    作者列表:Mannerberg A,Persson E,Jonsson J,Gustafsson CJ,Gunnlaugsson A,Olsson LE,Ceberg S
    BACKGROUND & AIMS: BACKGROUND:The purpose was to evaluate the dosimetric effects in prostate cancer treatment caused by anatomical changes occurring during the time frame of adaptive replanning in a magnetic resonance linear accelerator (MR-linac) workflow. METHODS:Two MR images (MR1 and MR2) were acquired with 30 min apart for each of the 35 patients enrolled in this study. The clinical target volume (CTV) and organs at risk (OARs) were delineated based on MR1. Using a synthetic CT (sCT), ultra-hypofractionated VMAT treatment plans were created for MR1, with three different planning target volume (PTV) margins of 7 mm, 5 mm and 3 mm. The three treatment plans of MR1, were recalculated onto MR2 using its corresponding sCT. The dose distribution of MR2 represented delivered dose to the patient after 30 min of adaptive replanning, omitting motion correction before beam on. MR2 was registered to MR1, using deformable registration. Using the inverse deformation, the structures of MR1 was deformed to fit MR2 and anatomical changes were quantified. For dose distribution comparison the dose distribution of MR2 was warped to the geometry MR1. RESULTS:The mean center of mass vector offset for the CTV was 1.92 mm [0.13 - 9.79 mm]. Bladder volume increase ranged from 12.4 to 133.0% and rectum volume difference varied between -10.9 and 38.8%. Using the conventional 7 mm planning target volume (PTV) margin the dose reduction to the CTV was 1.1%. Corresponding values for 5 mm and 3 mm PTV margin were 2.0% and 4.2% respectively. The dose to the PTV and OARs also decreased from D1 to D2, for all PTV margins evaluated. Statistically significant difference was found for CTV Dmin between D1 and D2 for the 3 mm PTV margin (p < 0.01). CONCLUSIONS:A target underdosage caused by anatomical changes occurring during the reported time frame for adaptive replanning MR-linac workflows was found. Volume changes in both bladder and rectum caused large prostate displacements. This indicates the importance of thorough position verification before treatment delivery and that the workflow needs to speed up before introducing margin reduction.
    背景与目标:
  • 【递归神经网络中的自适应时标。】 复制标题 收藏 收藏
    DOI:10.1038/s41598-020-68169-x 复制DOI
    作者列表:Quax SC,D'Asaro M,van Gerven MAJ
    BACKGROUND & AIMS: :Recent experiments have revealed a hierarchy of time scales in the visual cortex, where different stages of the visual system process information at different time scales. Recurrent neural networks are ideal models to gain insight in how information is processed by such a hierarchy of time scales and have become widely used to model temporal dynamics both in machine learning and computational neuroscience. However, in the derivation of such models as discrete time approximations of the firing rate of a population of neurons, the time constants of the neuronal process are generally ignored. Learning these time constants could inform us about the time scales underlying temporal processes in the brain and enhance the expressive capacity of the network. To investigate the potential of adaptive time constants, we compare the standard approximations to a more lenient one that accounts for the time scales at which processes unfold. We show that such a model performs better on predicting simulated neural data and allows recovery of the time scales at which the underlying processes unfold. A hierarchy of time scales emerges when adapting to data with multiple underlying time scales, underscoring the importance of such a hierarchy in processing complex temporal information.
    背景与目标: : 最近的实验揭示了视觉皮层中时间尺度的层次结构,视觉系统的不同阶段以不同的时间尺度处理信息。递归神经网络是理想的模型,可以洞悉如何通过这种时间尺度层次来处理信息,并且已广泛用于对机器学习和计算神经科学中的时间动力学进行建模。但是,在推导诸如神经元群体的放电速率的离散时间近似值之类的模型时,通常会忽略神经元过程的时间常数。学习这些时间常数可以使我们了解大脑中时间过程背后的时间尺度,并增强网络的表达能力。为了研究自适应时间常数的潜力,我们将标准近似值与更宽松的近似值进行了比较,该近似值说明了过程展开的时间尺度。我们证明,这样的模型在预测模拟神经数据方面表现更好,并且可以恢复基础过程展开的时间尺度。当适应具有多个基本时标的数据时,会出现时间尺度的层次结构,这突显了这种层次结构在处理复杂的时间信息中的重要性。
  • 【用H(infinity) 自适应算法提取胎儿心电图。】 复制标题 收藏 收藏
    DOI:10.1007/s11517-007-0235-5 复制DOI
    作者列表:Puthusserypady S
    BACKGROUND & AIMS: :The fetal electrocardiogram (fECG) contains important information regarding the health of the fetus. However, the fECG obtained noninvasively from the abdominal surface electrical recordings of a pregnant woman are dominated by strong interference from the maternal electrocardiogram (mECG). In this paper, based on the H(infinity) principle, two adaptive algorithms are proposed for the extraction of fECG from the trans-abdominal recordings of pregnant women. The motivation behind the application of H(infinity) techniques is the fact that they are robust with respect to model uncertainties and lack of statistical information regarding noise. The proposed algorithms are applied to simulated as well as real multichannel ECG recordings and their performances are compared to that of the well-known least-mean-square (LMS) adaptive algorithm. It is found that the proposed H(infinity) based algorithms perform superior to the LMS algorithm in extracting the fECG signal.
    背景与目标: : 胎儿心电图 (fECG) 包含有关胎儿健康的重要信息。然而,从孕妇的腹部表面电记录中无创获得的fECG主要受母体心电图 (mECG) 的强烈干扰。本文基于H(infinity) 原理,提出了两种自适应算法,用于从孕妇经腹记录中提取fECG。应用H(infinity) 技术的动机是,它们在模型不确定性和缺乏有关噪声的统计信息方面具有鲁棒性。将所提出的算法应用于模拟和真实的多通道ECG记录,并将其性能与众所周知的最小均方 (LMS) 自适应算法进行了比较。发现所提出的基于H(infinity) 的算法在提取fECG信号方面的性能优于LMS算法。

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