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kinetic-pharmacodynamic models: applications, limitations and perspectives: A systematic review 动力学-药效学模型:应用、局限性和前景:系统综述
Pub Date : 2023-11-14 DOI: 10.22541/au.169996507.76550842/v1
Leonardo Xavier, Sandro Filho, Izabel Alves
Pharmacometrics is instrumental in drug development, guiding decisions on dose selection, study design, formulation optimization, biomarker identification and commercial viability. While traditional Pharmacokinetic-Pharmacodynamic (PK/PD) modeling is widely embraced, Kinetic-Pharmacodynamic (KPD) modeling remains relatively underutilized. This paper introduces KPD modeling as an alternative approach for understanding dose-effect relationships in scenarios where conventional PK data is limited. KPD models use dose as the primary input to predict key parameters, offering a valuable tool for clinical applications. To explore KPD modeling’s scope and potential benefits, we conducted a systematic review following PRISMA guidelines. The research question was “Where can KPD modeling be applied, and what are the main outcomes from KPD models?”. We searched databases, including PubMed, Web of Science, Cochrane and EMBASE, using specific terms. Eligible articles had to be in english and discuss KPD modeling applications or its role in model development. Our review covered 132 articles published from January 2004 to October 2023, identifying 51 meeting inclusion criteria. Data included publication year, country, institution, study type, studied compounds, software tools, KPD applications, and outcomes. This paper presents a comprehensive analysis of reviewed studies, highlighting diverse KPD modeling applications in clinical and preclinical settings. It outlines limitations and suggests avenues for rational KPD integration into research, clinical trials, and regulatory approvals. By harnessing KPD modeling’s power, pharmacometrics can enhance decision-making, addressing challenges posed by limited PK data, ultimately advancing drug development and patient care.
药物计量学在药物开发、指导剂量选择、研究设计、配方优化、生物标志物鉴定和商业可行性方面发挥着重要作用。虽然传统的药代动力学-药效学(PK/PD)模型被广泛接受,但动力学-药效学(KPD)模型仍然相对未得到充分利用。本文介绍了KPD建模作为在常规PK数据有限的情况下理解剂量效应关系的替代方法。KPD模型使用剂量作为预测关键参数的主要输入,为临床应用提供了有价值的工具。为了探索KPD建模的范围和潜在的好处,我们按照PRISMA指南进行了系统的回顾。研究的问题是“KPD模型可以应用在哪里,KPD模型的主要结果是什么?”我们搜索数据库,包括PubMed, Web of Science, Cochrane和EMBASE,使用特定的术语。合格的文章必须是英文的,并且讨论KPD建模应用程序或其在模型开发中的作用。我们的综述涵盖了2004年1月至2023年10月期间发表的132篇文章,确定了51篇符合纳入标准。数据包括出版年份、国家、机构、研究类型、研究化合物、软件工具、KPD应用和结果。本文介绍了综述研究的综合分析,突出了临床和临床前环境中不同的KPD建模应用。它概述了局限性,并提出了将KPD合理整合到研究、临床试验和监管批准中的途径。通过利用KPD建模的力量,药物计量学可以增强决策,解决有限的PK数据带来的挑战,最终推进药物开发和患者护理。
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引用次数: 0
Characteristics of Precipitation and Mesoscale Convective Systems over the Peruvian Central Andes in Multi 5-Year Convection-Permitting Simulations 秘鲁安第斯中部降水和中尺度对流系统在多年对流模拟中的特征
Pub Date : 2023-11-14 DOI: 10.22541/essoar.170000370.07634797/v1
Yongjie Huang, Ming Xue, Xiao-Ming Hu, Elinor R Martin, Hector Mayol Novoa, Renee A. McPherson, Changhai Liu, Kyoko Ikeda, Roy Rasmussen, Andreas Franz Prein, Andres Vitaliano Perez, Isaac Yanqui Morales, José Luis Ticona, Auria Julieta Flores Luna
Using the Weather Research and Forecasting (WRF) model with two planetary boundary layer schemes, ACM2 and MYNN, convection-permitting model (CPM) regional climate simulations were conducted for a 6-year period at a 15-km grid spacing covering entire South America and a nested convection-permitting 3-km grid spacing covering the Peruvian central Andes region. These two CPM simulations along with a 4-km simulation covering South America produced by National Center for Atmospheric Research, three gridded global precipitation datasets, and rain gauge data in Peru and Brazil, are used to document the characteristics of precipitation and MCSs in the Peruvian central Andes region. Results show that all km-scale simulations generally capture the spatiotemporal patterns of precipitation and MCSs at both seasonal and diurnal scales, although biases exist in aspects such as precipitation intensity and MCS frequency, size, propagation speed, and associated precipitation intensity. The 3-km simulation using MYNN scheme generally outperforms the other simulations in capturing seasonal and diurnal precipitation over the mountain, while both it and the 4-km simulation demonstrate superior performance in the western Amazon Basin, based on the comparison to the gridded precipitation products and gauge data. Dynamic factors, primarily low-level jet and terrain-induced uplift, are the key drivers for precipitation and MCS genesis along the east slope of the Andes, while thermodynamic factors control the precipitation and MCS activity in the western Amazon Basin and over elevated mountainous regions. The study suggests aspects of the model needing improvement and the choice of better model configurations for future regional climate projections.
利用气候研究与预报(WRF)模式和两个行星边界层方案ACM2和MYNN,在覆盖整个南美洲的15 km网格间距和覆盖秘鲁中部安第斯地区的3 km嵌套对流网格间距上进行了6年的允许对流模式(CPM)区域气候模拟。这两个CPM模拟以及由国家大气研究中心制作的覆盖南美洲的4公里模拟、三个网格化全球降水数据集以及秘鲁和巴西的雨量计数据,用于记录秘鲁中部安第斯地区的降水和mcs特征。结果表明,尽管在降水强度、MCS频率、大小、传播速度和相关降水强度等方面存在偏差,但所有km尺度模拟在季节和日尺度上均能较好地捕捉降水和MCS的时空格局。基于网格化降水产品和实测数据的对比,3 km模式的MYNN模拟在山地季节降水和日降水方面总体上优于其他模拟,而在亚马孙盆地西部,3 km模式和4 km模式均表现出较好的模拟效果。动力因素(主要是低空急流和地形隆升)是安第斯山脉东坡降水和MCS形成的主要驱动因素,而热力因素控制亚马逊河流域西部和高山区降水和MCS活动。该研究提出了模式需要改进的方面,以及为未来区域气候预估选择更好的模式配置。
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引用次数: 0
Fun in the Sun: Singlet Oxygen Harnessing the Power of Light in Response to Biotic Stresses 阳光下的乐趣:单线态氧利用光的力量来应对生物压力
Pub Date : 2023-11-14 DOI: 10.22541/au.169999092.25614867/v1
Fiona L. Goggin, Hillary D. Fischer
Singlet Oxygen (SO) is among the most potent reactive oxygen species, and readily oxidizes proteins, lipids, and DNA. It can be generated at the plant surface by phototoxins in the epidermis, acting as a direct defense against pathogens and herbivores (including humans). SO can also accumulate within mitochondria, peroxisomes, cytosol, and the nucleus through multiple enzymatic and non-enzymatic processes. However, the primary location of SO in plants is in the chloroplast, where it results from transfer of light energy from PhotosystemII to triplet oxygen. SO accumulates in response to diverse stresses that perturb chloroplast metabolism, and while its short half-life precludes exiting the chloroplast, it participates in retrograde signaling through the EXECUTER1 sensor, generation of carotenoid metabolites, and possibly other unknown pathways. SO thereby reprograms nuclear gene expression and modulates hormone signaling and programmed cell death. While SO signaling has long been known to regulate plant responses to high-light stress, recent literature also suggests a role in plant interactions with insects, bacteria, and fungi. The goals of this review are to provide a brief overview of SO, summarize evidence for its involvement in biotic stress responses, and discuss future directions for the study of SO in signaling and defense.
单线态氧(SO)是最有效的活性氧之一,很容易氧化蛋白质、脂质和DNA。它可以在植物表面由表皮中的光毒素产生,作为对病原体和食草动物(包括人类)的直接防御。SO也可以通过多种酶和非酶过程在线粒体、过氧化物酶体、细胞质和细胞核内积累。然而,SO在植物中的主要位置是在叶绿体中,它是由光系统ii向三重态氧的光能转移产生的。SO的积累是对各种干扰叶绿体代谢的胁迫的反应,虽然它的半衰期很短,不能退出叶绿体,但它通过EXECUTER1传感器参与逆行信号传导,产生类胡萝卜素代谢物,以及可能的其他未知途径。因此,SO重编程核基因表达并调节激素信号传导和程序性细胞死亡。虽然人们早就知道SO信号可以调节植物对强光胁迫的反应,但最近的文献也表明,它在植物与昆虫、细菌和真菌的相互作用中也起作用。本文将简要介绍SO的研究概况,总结其参与生物应激反应的证据,并讨论其在信号传导和防御中的未来研究方向。
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引用次数: 0
Observations of reduced ET and persistent elevated water table beneath a riparian forest gap following emerald ash borer invasion and tree mortality 绿宝石灰蛀虫入侵和树木死亡后河岸林隙下ET减少和地下水位持续升高的观察
Pub Date : 2023-11-14 DOI: 10.22541/au.169999564.44755050/v1
Wendy Robertson, Sarah Krzemien, Patrick Engelken, Deborah G. McCullough
Emerald ash borer (EAB) ( Agrilus planipennis Fairmaire), an invasive, phloem-feeding beetle native to Asia, has killed millions of ash ( Fraxinus spp.) trees in North America since it was detected in southeast Michigan in 2002. Consistently high mortality of black ash ( Fraxinus nigra ) and green ash ( F. pennsylvanica ) which often occur in riparian forests is a concern given their role in regulating soil moisture and shallow groundwater levels. We monitored hydrologic processes in a riparian forest in southwest Michigan to assess impacts of EAB invasion and subsequent ash mortality. From 2018-2022, we recorded soil moisture, depth to groundwater and meteorological variables at 15-min intervals throughout the growing season in a canopy gap following EAB-caused ash mortality and in adjacent, unaffected forest in the Augusta Creek riparian zone. Groundwater contributions to evapotranspiration (ET ) were estimated using a groundwater level fluctuation (WLF) method. Significant differences in volumetric soil moisture content (16-26% higher in the gap than forest), average depth to water (10 cm in the gap vs 70 cm below land surface in the forest) and mean daily ET (0.6 in the gap vs 3.0 mm per day in the forest) persisted across four growing seasons. Within the gap, prolonged saturation of the near surface may be contributing to a shift from a forested riparian ecosystem to herb and sedge-dominated wetland. These differences have implications for an array of riparian zone ecosystem services, a concern given the extent of ash mortality already sustained in much eastern North America.
绿灰螟(EAB) (Agrilus planipennis Fairmaire)是一种原产于亚洲的入侵性韧皮部食性甲虫,自2002年在密歇根州东南部被发现以来,已经杀死了北美数百万棵白蜡树(蜡树属)。经常出现在河岸森林中的黑灰(黑蜡)和绿灰(F. pennsylvania)的死亡率一直很高,这是一个令人关切的问题,因为它们在调节土壤湿度和浅层地下水位方面起着作用。我们监测了密歇根西南部河岸森林的水文过程,以评估EAB入侵和随后的灰死亡率的影响。从2018年到2022年,我们在整个生长季节,在eab引起的白蜡死亡后的树冠间隙和奥古斯塔河河岸带邻近的未受影响的森林中,每隔15分钟记录一次土壤湿度、地下水深度和气象变量。利用地下水位波动法估算了地下水对蒸散发(ET)的贡献。在四个生长季节中,土壤体积含水量(林隙比森林高16-26%)、平均到水深度(林隙10厘米比森林地表以下70厘米)和平均日蒸散量(林隙0.6毫米比森林3.0毫米)的显著差异持续存在。在间隙内,近地表的长期饱和可能有助于从森林河岸生态系统向草本和莎草为主的湿地转变。这些差异对一系列河岸生态系统服务产生了影响,考虑到北美东部大部分地区已经持续的灰死亡率,这是一个令人担忧的问题。
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引用次数: 0
Vertical stratification of leaf physical traits exerts bottom-up pressures on insect herbivory in a sugar maple temperate forest 糖枫温带森林叶片物理特征的垂直分层对昆虫取食产生自下而上的压力
Pub Date : 2023-11-14 DOI: 10.22541/au.169995543.32413735/v1
Mahsa Hakimara, Emma Despland
Do vertical gradients structure temperate forest insect herbivore communities? We tested the hypothesis that the increase in light intensity from understory to forest canopy level drives differences in leaf physical traits and budburst phenology that impact insect herbivores and thus play a role in structuring both herbivore communities and the damage they cause to trees. Twelve sugar maple (Acer saccharum) trees were monitored in southern Quebec, examining herbivore patterns from understory to canopy. Three sampling sessions took place in the summers of 2020, 2021, and 2022, recording temperature, humidity, sun exposure, and leaf physical traits in three strata. In the first two years, we measured herbivory rates, quantifying affected leaf surface percentage by damage type. Overall, herbivory damage decreased from the understory to the shade canopy and sun canopy in 2020, driven by leaf cutters and skeletonizers. Leaf stipplers and blotch miners also followed this pattern in 2020. The 2021 sampling showed a similar, albeit weaker, pattern. Leaf cutters and skeletonizers consistently caused less damage with increasing height in the canopy. The abundance of insect herbivores collected in 2022 matched the observed damage trend. Leaf thickness increased along the vertical gradient, making leaves less accessible to herbivores. Variation in plant traits according to sun exposure thus contributes to explaining vertical stratification of insect herbivore damage. The average annual herbivory rate of 9.1% of leaf surface suggests limited evidence supporting an important contribution of background herbivory to the decline of sugar maple forests
垂直梯度是否构成温带森林昆虫食草动物群落?我们验证了这样一个假设,即从林下到林冠水平的光强增加驱动了叶片物理性状和芽物候的差异,这些差异影响了食草昆虫,从而在食草昆虫群落的结构和它们对树木造成的损害中发挥作用。对魁北克南部的12棵糖枫(Acer saccharum)树进行了监测,研究了从林下到树冠的食草动物模式。在2020年、2021年和2022年的夏季进行了三次采样,记录了三个地层的温度、湿度、阳光照射和叶片物理特征。在头两年,我们测量了草食率,根据损害类型量化了受影响的叶面百分比。总体而言,在切叶动物和骨架动物的驱动下,2020年草食损害从林下到遮荫冠层和遮阳冠层下降。2020年,树叶点画师和斑点矿工也遵循了这种模式。2021年的抽样显示出类似的模式,尽管较弱。随着树冠高度的增加,切叶者和骷髅者造成的伤害也越来越小。2022年收集的食草昆虫的丰度与观察到的损害趋势相符。叶片厚度沿垂直梯度增加,使得食草动物更难接近叶片。植物性状随日照的变化有助于解释昆虫食草损害的垂直分层。叶表面年平均草食率为9.1%,表明背景草食对糖枫林的衰落有重要贡献的证据有限
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引用次数: 0
Foundation Models in shaping the future of ecology 塑造未来生态学的基础模型
Pub Date : 2023-11-14 DOI: 10.22541/au.169996552.25188347/v1
Albert Morera
In the field of ecology, we are facing urgent challenges related to biodiversity loss, global change and ecosystem sustainability. In this context, the application of Foundation Models emerges as a powerful tool. These models have the potential to reshape our understanding of natural systems, incorporating large volumes of data from different sources and generating results with a more holistic view of ecosystem functioning. However, the application of foundational models in ecology presents challenges that will need to be addressed, such as model interpretation, training efficiency, and the ethical considerations due their implementation.
在生态学领域,我们正面临着与生物多样性丧失、全球变化和生态系统可持续性相关的紧迫挑战。在这种情况下,基础模型的应用程序作为一个强大的工具出现。这些模型有可能重塑我们对自然系统的理解,整合来自不同来源的大量数据,并以更全面的生态系统功能视角产生结果。然而,基础模型在生态学中的应用提出了需要解决的挑战,例如模型解释,训练效率以及由于其实施而引起的伦理考虑。
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引用次数: 0
A case for the use of chemotherapy in hereditary optic neuropathies: successful administration of cisplatin/etoposide in a male patient with testicular seminoma and Leber’s Hereditary Optic Neuropathy 遗传性视神经病变化疗一例:顺铂/依托泊苷成功治疗睾丸精原细胞瘤和Leber遗传性视神经病变的男性患者
Pub Date : 2023-11-14 DOI: 10.22541/au.169996525.59629438/v1
Jean-Luc Vrisakis, Clare Fraser, Udit Nindra, Adel Shahnam, Peter Grimison
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引用次数: 0
A one-year-old boy with cystic teratoma mimicking simple testicular cyst : A rare case report from Syria. 1岁男童囊性畸胎瘤,似单纯性睾丸囊肿:叙利亚罕见病例报告。
Pub Date : 2023-11-14 DOI: 10.22541/au.169994287.78003281/v1
Hasan Alsmodi, Mouhammed Sleiay, Bilal Sleiay, Abdulazez Sleiay, Abdalrahman Slaea, Gihad Allugamie
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引用次数: 0
Forecasting Animal Distribution through Individual Habitat Selection: Insights for Population Inference and Transferable Predictions 通过个体栖息地选择预测动物分布:种群推断和可转移预测的见解
Pub Date : 2023-11-14 DOI: 10.22541/au.169997309.95502508/v1
Veronica Winter, Brian Smith, Danielle Berger, Ronan Hart, John Huang, Kezia Manlove, Frances Buderman, Tal Avgar
Species distribution and habitat selection models frequently use data collected from a small geographic area over a short window of time to extrapolate patterns of relative abundance to unobserved areas or periods of time. However, these types of models often poorly predict how animals will use habitat beyond the place and time of data collection because space-use behaviors vary between individuals and are context-dependent. Here, we present a modelling workflow to advance predictive distribution performance by explicitly accounting for individual variability in habitat selection behavior and dependence on environmental context. Using global positioning system (GPS) data collected from 238 individual pronghorn, (Antilocapra americana), across 3 years in Utah, we combine individual-year-season-specific exponential habitat-selection models with weighted mixed-effects regressions to both draw inference about the drivers of habitat selection and predict space-use in areas/times where/when pronghorn were not monitored. We found a tremendous amount of variation in both the magnitude and direction of habitat selection behavior across seasons, but also across individuals, geographic regions, and years. We were able to attribute portions of this variation to season, movement strategy, sex, and regional variability in resources, conditions, and risks. We were also able to partition residual variation into inter- and intra-individual components. We then used the results to predict population-level, spatially and temporally dynamic, habitat-selection coefficients across Utah, resulting in a temporally dynamic map of pronghorn distribution at a 30x30m resolution but an extent of 220,000km2. We believe our transferable workflow can provide managers and researchers alike a way to turn limitations of traditional RSF models - variability in habitat selection - into a tool to improve understanding and predicting animal distribution across space and time.
物种分布和生境选择模型经常使用在短时间内从小地理区域收集的数据来推断未观察到的区域或时间段的相对丰度模式。然而,这些类型的模型往往不能很好地预测动物将如何在数据收集的地点和时间之外使用栖息地,因为个体之间的空间使用行为是不同的,并且依赖于环境。在这里,我们提出了一个建模工作流程,通过明确地考虑栖息地选择行为的个体可变性和对环境背景的依赖,来提高预测分布的性能。利用美国犹他州238只叉角羚(Antilocapra americana) 3年的全球定位系统(GPS)数据,将个体-季节-特定指数栖息地选择模型与加权混合效应回归相结合,得出栖息地选择驱动因素的推断,并预测叉角羚未被监测的地区/时间的空间利用情况。我们发现,在栖息地选择行为的大小和方向上,不同季节、不同个体、不同地理区域和不同年份都有巨大的差异。我们能够将这种变化部分归因于季节、运动策略、性别和资源、条件和风险的区域差异。我们还能够将剩余变异划分为个体之间和个体内部的成分。然后,我们利用结果预测了整个犹他州的种群水平、时空动态、栖息地选择系数,得到了一张分辨率为30x30m、面积为220,000km2的叉角羚时空动态分布图。我们相信,我们的可转移工作流程可以为管理者和研究人员提供一种方法,将传统RSF模型的局限性——栖息地选择的可变性——转化为一种工具,以提高对动物在空间和时间上分布的理解和预测。
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引用次数: 0
Multi-dimensional Hydrogen Bonds Regulated Emissions of Single Molecule Enabling Hydrophobicity/Hydrophilicity Mapping 多维氢键调节单分子的发射,实现疏/亲水性作图
Pub Date : 2023-11-14 DOI: 10.22541/au.169993455.58667966/v1
Hao Gu, Rui Li, Qiuying Li, Sheng Lu, Yahui Chen, Xiaoning Yang, Huili Ma, Zhijun Xu, Xiaoqiang Chen
Constructing multi-dimensional hydrogen bond (H-bond) regulated single-molecule systems with multi-emission remains a challenge. Herein, we report an excited-excited intramolecular transfer (ESIPT) featured chromophore (HBT-DPI) that shows flexible emission tunability via the multi-dimensional regulation of intra- and intermolecular H-bonds. The feature of switchable intramolecular H-bonds is induced via incorporating two hydrogen bond acceptors into a single-molecule system, HBT-DPI, allowing the “turn on/off” of ESIPT process by forming isomers with distinct intramolecular H-bonds. In response to different solvent environments, the obtained four types of crystal/cocrystals vary in the contents of isomers and the molecular packing modes, which are mainly guided by the intermolecular H-bonds, exhibiting non-emissive features or emissions ranging from green to orange. Moreover, we demonstrate the practical utility of this fluorescent material for visualizing hydrophobic/hydrophilic areas on large-scale heterogeneous surfaces of modified PVDF membranes and quantitatively estimate the surface hydrophobicity, providing a new approach for hydrophobicity/hydrophilicity monitoring and measurement.
构建多维氢键调控的多发射单分子体系仍然是一个挑战。在此,我们报道了一种具有激发态-激发态分子内转移(ESIPT)特征的发色团(HBT-DPI),它通过分子内和分子间氢键的多维调节显示出灵活的发射可调性。通过将两个氢键受体结合到单分子体系hpt - dpi中,诱导了分子内氢键可切换的特征,通过形成具有不同分子内氢键的异构体,允许ESIPT过程的“开启/关闭”。在不同的溶剂环境下,得到的四种晶体/共晶在异构体的含量和分子填充模式上有所不同,主要由分子间氢键引导,表现出非发射特征或从绿色到橙色的发射。此外,我们还展示了该荧光材料在改性PVDF膜的大规模非均相表面上的疏水/亲水区域可视化和定量估计表面疏水性的实用性,为疏水/亲水性监测和测量提供了一种新的方法。
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引用次数: 0
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