治疗药物监测(Therapeutic drug monitoring,TDM),如通过定量测定血清或血浆药物浓度指导用药剂量优化,已经成为对患者进行精神药物治疗的很有价值的工具。在患者用药依从性难以判断、药物耐受性不佳、治疗剂量下无效以及可能存在药代...治疗药物监测(Therapeutic drug monitoring,TDM),如通过定量测定血清或血浆药物浓度指导用药剂量优化,已经成为对患者进行精神药物治疗的很有价值的工具。在患者用药依从性难以判断、药物耐受性不佳、治疗剂量下无效以及可能存在药代动力学药物-药物相互作用等情况下,测定药物浓度是很有用的。在精神科,有可能明显获益于TDM的主要患者群体包括儿童、孕妇、老年患者、智力障碍患者、涉及司法的患者、已知或怀疑携带药代动力学相关基因变异的患者,以及合并躯体疾病影响药代动力学的患者。然而,只有将TDM充分整合到临床治疗过程中去,才能发挥其优化药物治疗的潜在优势。为了促进TDM的合理应用,神经精神药理学与药物精神病学协会(Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie,AGNP)的TDM专家组在2004年发表了精神药物治疗药物监测指南。之后,随着知识不断更新,又有许多可能需要进行TDM的新药上市。因此,本次更新将神经精神药物的种类扩展到了128种,并将其TDM必要性划分为从"强烈推荐"到"可能有用"的四个等级。经过大量细致且全面的文献检索与分门别类的汇总整理,将基于循证医学理念的"治疗参考浓度范围"和"剂量相关参考浓度范围"呈现给大家。本共识指南引入了"实验室警戒浓度"的新概念,即实验室需要马上告知治疗医生的药物浓度上限。本共识指南还给出了诸如药物作为细胞色素P450酶的底物和抑制剂的性质,代谢物与母药浓度比值的常见范围,以及与结果解释相关的内容,还提供了何时将TDM与遗传药理学检测相结合的建议。遵循本指南,有助于改善许多患者精神药物治疗的效果,特别是那些存在药代动力学异常的患者。TDM是一门交叉学科,有时针对看起来不一致的数据,需要多学科坦诚地讨论,只有这样,患者才能从这种合作中展开更多
治疗药物监测(Therapeutic Drug Monitoring,TDM)通过定量测定和解释血药浓度以优化药物治疗。TDM着眼于药代动力学的个体差异,使个体化药物治疗成为可能。在精神病学和神经病学领域中,有可能明显获益于TDM的主要患者群体包括少年儿童...治疗药物监测(Therapeutic Drug Monitoring,TDM)通过定量测定和解释血药浓度以优化药物治疗。TDM着眼于药代动力学的个体差异,使个体化药物治疗成为可能。在精神病学和神经病学领域中,有可能明显获益于TDM的主要患者群体包括少年儿童、孕妇、老年患者、智障患者、药物滥用者、涉法精神病患者、已知或怀疑药代动力学异常的患者以及合并躯体疾病影响药代动力学的患者。常规剂量下治疗无效,用药依从性难以判断,药物耐受性不佳,以及可能存在药代动力学方面的药物-药物相互作用等情况都是治疗药物监测的典型指征。然而,只有将TDM充分整合到临床治疗过程中,才能发挥其优化药物治疗的潜在优势。为了向临床医生和实验室提供有效的TDM信息,神经精神药理学与药物精神病学协会(Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie,AGNP)的TDM专家组在2004年发表了第一版《精神科治疗药物监测指南》。2011年进行了更新之后,现在再次更新。遵循新版指南,可能会改善神经精神药物治疗的效果,加快很多患者的康复,并降低医疗费用。展开更多
Grapevine is one of the most economically important crops worldwide.However,the previous versions of the grapevine reference genome tipically consist of thousands of fragments with missing centromeres and telomeres,li...Grapevine is one of the most economically important crops worldwide.However,the previous versions of the grapevine reference genome tipically consist of thousands of fragments with missing centromeres and telomeres,limiting the accessibility of the repetitive sequences,the centromeric and telomeric regions,and the study of inheritance of important agronomic traits in these regions.Here,we assembled a telomere-to-telomere(T2T)gap-free reference genome for the cultivar PN40024 using PacBio HiFi long reads.The T2T reference genome(PN_T2T)is 69 Mb longer with 9018 more genes identified than the 12X.v0 version.We annotated 67%repetitive sequences,19 centromeres and 36 telomeres,and incorporated gene annotations of previous versions into the PN_T2T assembly.We detected a total of 377 gene clusters,which showed associations with complex traits,such as aroma and disease resistance.Even though PN40024 derives from nine generations of selfing,we still found nine genomic hotspots of heterozygous sites associated with biological processes,such as the oxidation–reduction process and protein phosphorylation.The fully annotated complete reference genome therefore constitutes an important resource for grapevine genetic studies and breeding programs.展开更多
Super-resolution structured illumination microscopy(SR-SIM) provides an up to twofold enhanced spatial resolution of fluorescently labeled samples. The reconstruction of high-quality SR-SIM images critically depends o...Super-resolution structured illumination microscopy(SR-SIM) provides an up to twofold enhanced spatial resolution of fluorescently labeled samples. The reconstruction of high-quality SR-SIM images critically depends on patterned illumination with high modulation contrast. Noisy raw image data(e.g., as a result of low excitation power or low exposure time), result in reconstruction artifacts. Here, we demonstrate deep-learning based SR-SIM image denoising that results in high-quality reconstructed images. A residual encoding–decoding convolutional neural network(RED-Net) was used to successfully denoise computationally reconstructed noisy SR-SIM images.We also demonstrate the end-to-end deep-learning based denoising and reconstruction of raw SIM images into high-resolution SR-SIM images. Both image reconstruction methods prove to be very robust against image reconstruction artifacts and generalize very well across various noise levels. The combination of computational image reconstruction and subsequent denoising via RED-Net shows very robust performance during inference after training even if the microscope settings change.展开更多
N^6-methyladenosine(m^6A)emerges as an important modification in eukaryotic mRNAs.m^6A has first been reported in 1974,and its functional significance in mammalian gene regulation and importance for proper development...N^6-methyladenosine(m^6A)emerges as an important modification in eukaryotic mRNAs.m^6A has first been reported in 1974,and its functional significance in mammalian gene regulation and importance for proper development have been well established.An arsenal of writer,eraser,and reader proteins accomplish deposition,removal,and interpretation of the m^6A mark,resulting in dynamic function.This led to the concept of an epitranscriptome,the compendium of RNA species with chemical modification ofthe nucleobases in the cell,in analogy to the epigenome.While m^6A has long been known to also exist in plant mRNAs,proteins involved in m^6A metabolism have only recently been detected by mutant analysis,homology search,and mRNA interactome capture in the reference plant Arabidopsis thaliana.Dysregulation ofthe m^6A modification causes severe developmental abnormalities of leaves and roots and altered timing of reproductive development.Furthermore,m^6A modification affects viral infection.Here,we discuss recent progress in identifying m^6A sites transcriptome-wide,in identifying the molecular players involved in writing,removing,and reading the mark,and in assigning functions to this RNA modification in 4.thaliana.We highlight similarities and differences to m^6A modification in mammals and provide an outlook on important questions that remain to be addressed.展开更多
The stress-associated protein SAP12 belongs to the stress-associated protein （SAP） family with 14 members in Arabidopsis thaliana. SAP12 contains two AN1 zinc fingers and was identified in diagonal 2D redox SDS-PAGE...The stress-associated protein SAP12 belongs to the stress-associated protein （SAP） family with 14 members in Arabidopsis thaliana. SAP12 contains two AN1 zinc fingers and was identified in diagonal 2D redox SDS-PAGE as a protein undergoing major redox-dependent conformational changes. Its transcript was strongly induced under cold and salt stress in a time-dependent manner similar to SAP10, with high levels after 6 h and decreasing levels after 24 and 48 h. The tran- script regulation resembled those of the stress marker peroxiredoxin PrxllD at 24 and 48 h. Recombinant SAP12 protein showed redox-dependent changes in quaternary structure as visualized by altered electrophoretic mobility in non-reducing SDS polyacrylamide gel electrophoresis. The oxidized oligomer was reduced by high dithiothreitol concentrations, and also by E. coli thioredoxin TrxA with low dithiothreitol （DTF） concentrations or NADPH plus NADPH-dependent thioredoxin reductase. From Western blots, the SAP12 protein amount was estimated to be in the range of 0.5 ngμg^-1 leaf protein. SAP12 protein decreased under salt and cold stress. These data suggest a redox state-linked function of SAP12 in plant cells particularly under cold and salt stress.展开更多
Let G =(V,E) be a locally finite graph,whose measure μ(x) has positive lower bound,and A be the usual graph Laplacian.Applying the mountain-pass theorem due to Ambrosetti and Rabinowitz(1973),we establish existence r...Let G =(V,E) be a locally finite graph,whose measure μ(x) has positive lower bound,and A be the usual graph Laplacian.Applying the mountain-pass theorem due to Ambrosetti and Rabinowitz(1973),we establish existence results for some nonlinear equations,namely △u+hu=f(x,u),x∈V.In particular,we prove that if h and f satisfy certain assumptions,then the above-mentioned equation has strictly positive solutions.Also,we consider existence of positive solutions of the perturbed equation △u+hu=f(x,u)+∈g.Similar problems have been extensively studied on the Euclidean space as well as on Riemannian manifolds.展开更多
The development of zero and negative therma expansion(i.e.,ZTE and NTE)materials is of crucial importance to the control of undesirable thermal expansion for high-precision devices.In the present work,ZTE and NTE were...The development of zero and negative therma expansion(i.e.,ZTE and NTE)materials is of crucial importance to the control of undesirable thermal expansion for high-precision devices.In the present work,ZTE and NTE were obtained in directionally-solidified Mn_(x)Fe_(5-x)Si_(3)alloys with a strong<001>texture,in striking contrast to positive thermal expansion in their isotropic counterparts Magnetometry and in-situ X-ray diffraction(XRD)measurements were performed to uncover the origin of the anomalous thermal expansion.Magnetic measurements indicate a strong easy-plane magnetocrystalline anisotropy in the textured samples,where the magnetic moments are aligned within the ab plane of the hexagonal structure Temperature-dependent XRD on the x=1 sample reveals a ZTE character in the ab plane that is coupled to a ferromagnetic transition.As a result,the macroscopic ZTE(~0.22×10^(-6)K^(-1))in the x=1 sample can be attributed to the microscopic magneto volume effect within the ab plane,which is realized by the introduction of the<001>-textured microstructure.Besides,the competition between antiferromagnetic and ferromagnetic exchange coupling leads to NTE in textured x=1.5 and 2 samples.Additionally,textured x=1 sample displays enhanced magnetocaloric properties as compared to the conventional counterparts with randomly-oriented grains.Consequently this work demonstrates a new strategy toward the exploration of anomalous thermal expansion properties as well as the enhancement of magnetocaloric properties for materials with a strong magnetocrystalline anisotropy.展开更多
Urbanization occurs at a global scale,imposing dramatic and abrupt environmental changes that lead to biodiversity loss.Yet,some animal species can handle these changes,and thrive in such artifcial environments.One po...Urbanization occurs at a global scale,imposing dramatic and abrupt environmental changes that lead to biodiversity loss.Yet,some animal species can handle these changes,and thrive in such artifcial environments.One possible explanation is that urban individuals are equipped with better cognitive abilities,but most studies have focused on birds and mammals and yielded varied results.Reptiles have received much less attention,despite some lizard species being common city dwellers.The Italian wall lizard,Podarcis siculus,and the common wall lizard,Podarcis muralis,are two successful lizards in anthropogenic habitats that thrive in urban locations.To test for differences in a cognitive skill between urban and semi-natural environments,we investigated inhibitory control through a detour task in syntopic populations of the two species,across 249 lizards that were tested in partially artifcial feld settings.Sophisticated inhibitory control is considered essential for higher degrees of cognitive fexibility and other higher-level cognitive abilities.In this task,we confronted lizards with a transparent barrier,separating them from a desired shelter area that they could only reach by controlling their impulse to go straight and instead detour the barrier.We found no differences between lizards in urban and semi-natural environments,nor between species,but females overall performed better than males.Moreover,48%of the lizards in our study did not perform a correct trial in any of the 5 trials,hinting at the diffculty of the task for these species.This study is among the frst to address lizard cognition,through their inhibitory control,as a potential explanation for success in cities and highlights one should be careful with assuming that urban animals generally have enhanced cognitive performance,as it might be taxa,task,or condition dependent.展开更多
The recent rapid development of deep learning has laid a milestone in industrial image anomaly detection(IAD).In this pa-per,we provide a comprehensive review of deep learning-based image anomaly detection techniques,...The recent rapid development of deep learning has laid a milestone in industrial image anomaly detection(IAD).In this pa-per,we provide a comprehensive review of deep learning-based image anomaly detection techniques,from the perspectives of neural net-work architectures,levels of supervision,loss functions,metrics and datasets.In addition,we extract the promising setting from indus-trial manufacturing and review the current IAD approaches under our proposed setting.Moreover,we highlight several opening chal-lenges for image anomaly detection.The merits and downsides of representative network architectures under varying supervision are discussed.Finally,we summarize the research findings and point out future research directions.More resources are available at https://github.com/M-3LAB/awesome-industrial-anomaly-detection.展开更多
Changes in ambient temperature profoundly affect plant growth and performance.Therefore,the molecu-larbasis of plant acclimation to temperature fluctuation is of great interest.In this study,we discovered that GLYCINE...Changes in ambient temperature profoundly affect plant growth and performance.Therefore,the molecu-larbasis of plant acclimation to temperature fluctuation is of great interest.In this study,we discovered that GLYCINE-RICH RNA-BINDING PROTEIN 7(GRP7)contributes to cold and heat tolerance in Arabidopsis thaliana.We found that exposure to a warm temperature rapidly induces GRP7 condensates in planta,which can be reversed by transfer to a lower temperature.Cell biology and biochemical assays revealed that GRP7 undergoes liquid-liquid phase separation(LLPS)in vivo and in vitro.LLPS of GRP7 in the cyto-plasm contributes to the formation of stress granules that recruit RNA,along with the translation machinery component eukaryotic initiation factor 4E1(elF4E1)and the mRNA chaperones COLD SHOCK PROTEIN 1(CSP1)and CSP3,to inhibit translation.Moreover,natural variations in GRP7 affecting the residue phos-phorylated by the receptorkinase FERONIA alter its capacity to undergo LLPS and correlate with the adap-tation of some Arabidopsis accessions to a widertemperature range.Taken together,ourfindings illustrate the role of translational control mediated by GRP7 LLPS to confer plants with temperature resilience.展开更多
With the development of edge devices and cloud computing,the question of how to accomplish machine learning and optimization tasks in a privacy-preserving and secure way has attracted increased attention over the past...With the development of edge devices and cloud computing,the question of how to accomplish machine learning and optimization tasks in a privacy-preserving and secure way has attracted increased attention over the past decade.As a privacy-preserving distributed machine learning method,federated learning(FL)has become popular in the last few years.However,the data privacy issue also occurs when solving optimization problems,which has received little attention so far.This survey paper is concerned with privacy-preserving optimization,with a focus on privacy-preserving data-driven evolutionary optimization.It aims to provide a roadmap from secure privacy-preserving learning to secure privacy-preserving optimization by summarizing security mechanisms and privacy-preserving approaches that can be employed in machine learning and optimization.We provide a formal definition of security and privacy in learning,followed by a comprehensive review of FL schemes and cryptographic privacy-preserving techniques.Then,we present ideas on the emerging area of privacy-preserving optimization,ranging from privacy-preserving distributed optimization to privacy-preserving evolutionary optimization and privacy-preserving Bayesian optimization(BO).We further provide a thorough security analysis of BO and evolutionary optimization methods from the perspective of inferring attacks and active attacks.On the basis of the above,an in-depth discussion is given to analyze what FL and distributed optimization strategies can be used for the design of federated optimization and what additional requirements are needed for achieving these strategies.Finally,we conclude the survey by outlining open questions and remaining challenges in federated data-driven optimization.We hope this survey can provide insights into the relationship between FL and federated optimization and will promote research interest in secure federated optimization.展开更多
Coherent Raman scattering(CRS)microscopy is widely recognized as a powerful tool for tackling biomedical problems based on its chemically specific label-free contrast,high spatial and spectral resolution,and high sens...Coherent Raman scattering(CRS)microscopy is widely recognized as a powerful tool for tackling biomedical problems based on its chemically specific label-free contrast,high spatial and spectral resolution,and high sensitivity.However,the clinical translation of CRS imaging technologies has long been hindered by traditional solid-state lasers with environmentally sensitive operations and large footprints.Ultrafast fibre lasers can potentially overcome these shortcomings but have not yet been fully exploited for CRS imaging,as previous implementations have suffered from high intensity noise,a narrow tuning range and low power,resulting in low image qualities and slow imaging speeds.Here,we present a novel high-power self-synchronized two-colour pulsed fibre laser that achieves excellent performance in terms of intensity stability(improved by 50 dB),timing jitter(24.3 fs),average power fluctuation(<0.5%),modulation depth(>20 dB)and pulse width variation(<1.8%)over an extended wavenumber range(2700-3550 cm^(−1)).The versatility of the laser source enables,for the first time,high-contrast,fast CRS imaging without complicated noise reduction via balanced detection schemes.These capabilities are demonstrated in this work by imaging a wide range of species such as living human cells and mouse arterial tissues and performing multimodal nonlinear imaging of mouse tail,kidney and brain tissue sections by utilizing second-harmonic generation and twophoton excited fluorescence,which provides multiple optical contrast mechanisms simultaneously and maximizes the gathered information content for biological visualization and medical diagnosis.This work also establishes a general scenario for remodelling existing lasers into synchronized two-colour lasers and thus promotes a wider popularization and application of CRS imaging technologies.展开更多
In plants, the highly abundant 2-cysteine peroxiredoxin （2-CysPrx） is associated with the chloroplast and involved in protecting photosynthesis. This work addresses the multiple interactions of the 2-CysPrx in the c...In plants, the highly abundant 2-cysteine peroxiredoxin （2-CysPrx） is associated with the chloroplast and involved in protecting photosynthesis. This work addresses the multiple interactions of the 2-CysPrx in the chloroplast, which depend on its redox state. Transcript co-regulation analysis showed a strong linkage to the peptidyl-prolyl-cis/trans isomerase Cyclophilin 20-3 （Cyp20-3） and other components of the photosynthetic apparatus. Co-expression in protoplasts and quantification of fluorescence resonance energy transfer （FRET） efficiency in vivo confirmed protein interactions of 2-CysPrx with Cyp20-3 as well as NADPH-dependent thioredoxin reductase C （NTRC）, while thioredoxin x （Trx-x） did not form complexes that could enable FRET. Likewise, changes in FRET of fluorescently labeled 2-CysPrx in vitro and in vivo proved redox dependent dynamics of 2-CysPrx. Addition of Cyp20-3 to an in vitro peroxidase assay with 2-CysPrx had no significant effect on peroxide reduction. Also, in the presence of NTRC, addition of Cyp20-3 did not further enhance peroxide reduction. In addition, 2-CysPrx functioned as chaperone and inhibited aggregation of citrate synthase during heat treatment. This activity was partly inhibited by Cyp20-3. As a new interaction partner of decameric 2-CysPrx, photosystem Ⅱ could be identified after chloroplast fractionation and in pull-down assays after reconstitution. In summary, the data indicate a dynamic function of plant 2-CysPrx as redox sensor, chaperone, and regulator in the chloroplast with diverse functions beyond its role as thiol peroxidase.展开更多
Cluster of differentiation 74(CD74),also called as major histocompatibility complex class Ⅱ(MHCⅡ)invariant chain,is involved in trafficking MHCⅡ cell surface molecules on antigen-presenting cells and has been impli...Cluster of differentiation 74(CD74),also called as major histocompatibility complex class Ⅱ(MHCⅡ)invariant chain,is involved in trafficking MHCⅡ cell surface molecules on antigen-presenting cells and has been implicated in many signaling pathways.For example,the interaction between CD74 and macrophage migration inhibitory factor cyto kine(MIF) leads to the activation of a plethora of pathways such as extracellular regulated protein kinases,phosphoinositide 3-kinase.展开更多
Solving constrained multi-objective optimization problems with evolutionary algorithms has attracted considerable attention.Various constrained multi-objective optimization evolutionary algorithms(CMOEAs)have been dev...Solving constrained multi-objective optimization problems with evolutionary algorithms has attracted considerable attention.Various constrained multi-objective optimization evolutionary algorithms(CMOEAs)have been developed with the use of different algorithmic strategies,evolutionary operators,and constraint-handling techniques.The performance of CMOEAs may be heavily dependent on the operators used,however,it is usually difficult to select suitable operators for the problem at hand.Hence,improving operator selection is promising and necessary for CMOEAs.This work proposes an online operator selection framework assisted by Deep Reinforcement Learning.The dynamics of the population,including convergence,diversity,and feasibility,are regarded as the state;the candidate operators are considered as actions;and the improvement of the population state is treated as the reward.By using a Q-network to learn a policy to estimate the Q-values of all actions,the proposed approach can adaptively select an operator that maximizes the improvement of the population according to the current state and thereby improve the algorithmic performance.The framework is embedded into four popular CMOEAs and assessed on 42 benchmark problems.The experimental results reveal that the proposed Deep Reinforcement Learning-assisted operator selection significantly improves the performance of these CMOEAs and the resulting algorithm obtains better versatility compared to nine state-of-the-art CMOEAs.展开更多
Mucopolysaccharidoses(MPS)are a group of rare inborn errors of metabolism caused by defective lysosomal enzymes which prevent cells from degrading and recycling certain carbohydrates and fats,resulting in the storage ...Mucopolysaccharidoses(MPS)are a group of rare inborn errors of metabolism caused by defective lysosomal enzymes which prevent cells from degrading and recycling certain carbohydrates and fats,resulting in the storage of glycosaminoglycans in cells throughout the body.This leads to multisystem abnormalities involving bone,connective tissues,brain,blood,spinal cord,skin,and other tissues.展开更多
Large-scale multi-objective optimization problems(LSMOPs)pose challenges to existing optimizers since a set of well-converged and diverse solutions should be found in huge search spaces.While evolutionary algorithms a...Large-scale multi-objective optimization problems(LSMOPs)pose challenges to existing optimizers since a set of well-converged and diverse solutions should be found in huge search spaces.While evolutionary algorithms are good at solving small-scale multi-objective optimization problems,they are criticized for low efficiency in converging to the optimums of LSMOPs.By contrast,mathematical programming methods offer fast convergence speed on large-scale single-objective optimization problems,but they have difficulties in finding diverse solutions for LSMOPs.Currently,how to integrate evolutionary algorithms with mathematical programming methods to solve LSMOPs remains unexplored.In this paper,a hybrid algorithm is tailored for LSMOPs by coupling differential evolution and a conjugate gradient method.On the one hand,conjugate gradients and differential evolution are used to update different decision variables of a set of solutions,where the former drives the solutions to quickly converge towards the Pareto front and the latter promotes the diversity of the solutions to cover the whole Pareto front.On the other hand,objective decomposition strategy of evolutionary multi-objective optimization is used to differentiate the conjugate gradients of solutions,and the line search strategy of mathematical programming is used to ensure the higher quality of each offspring than its parent.In comparison with state-of-the-art evolutionary algorithms,mathematical programming methods,and hybrid algorithms,the proposed algorithm exhibits better convergence and diversity performance on a variety of benchmark and real-world LSMOPs.展开更多
文摘治疗药物监测(Therapeutic drug monitoring,TDM),如通过定量测定血清或血浆药物浓度指导用药剂量优化,已经成为对患者进行精神药物治疗的很有价值的工具。在患者用药依从性难以判断、药物耐受性不佳、治疗剂量下无效以及可能存在药代动力学药物-药物相互作用等情况下,测定药物浓度是很有用的。在精神科,有可能明显获益于TDM的主要患者群体包括儿童、孕妇、老年患者、智力障碍患者、涉及司法的患者、已知或怀疑携带药代动力学相关基因变异的患者,以及合并躯体疾病影响药代动力学的患者。然而,只有将TDM充分整合到临床治疗过程中去,才能发挥其优化药物治疗的潜在优势。为了促进TDM的合理应用,神经精神药理学与药物精神病学协会(Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie,AGNP)的TDM专家组在2004年发表了精神药物治疗药物监测指南。之后,随着知识不断更新,又有许多可能需要进行TDM的新药上市。因此,本次更新将神经精神药物的种类扩展到了128种,并将其TDM必要性划分为从"强烈推荐"到"可能有用"的四个等级。经过大量细致且全面的文献检索与分门别类的汇总整理,将基于循证医学理念的"治疗参考浓度范围"和"剂量相关参考浓度范围"呈现给大家。本共识指南引入了"实验室警戒浓度"的新概念,即实验室需要马上告知治疗医生的药物浓度上限。本共识指南还给出了诸如药物作为细胞色素P450酶的底物和抑制剂的性质,代谢物与母药浓度比值的常见范围,以及与结果解释相关的内容,还提供了何时将TDM与遗传药理学检测相结合的建议。遵循本指南,有助于改善许多患者精神药物治疗的效果,特别是那些存在药代动力学异常的患者。TDM是一门交叉学科,有时针对看起来不一致的数据,需要多学科坦诚地讨论,只有这样,患者才能从这种合作中
文摘治疗药物监测(Therapeutic Drug Monitoring,TDM)通过定量测定和解释血药浓度以优化药物治疗。TDM着眼于药代动力学的个体差异,使个体化药物治疗成为可能。在精神病学和神经病学领域中,有可能明显获益于TDM的主要患者群体包括少年儿童、孕妇、老年患者、智障患者、药物滥用者、涉法精神病患者、已知或怀疑药代动力学异常的患者以及合并躯体疾病影响药代动力学的患者。常规剂量下治疗无效,用药依从性难以判断,药物耐受性不佳,以及可能存在药代动力学方面的药物-药物相互作用等情况都是治疗药物监测的典型指征。然而,只有将TDM充分整合到临床治疗过程中,才能发挥其优化药物治疗的潜在优势。为了向临床医生和实验室提供有效的TDM信息,神经精神药理学与药物精神病学协会(Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie,AGNP)的TDM专家组在2004年发表了第一版《精神科治疗药物监测指南》。2011年进行了更新之后,现在再次更新。遵循新版指南,可能会改善神经精神药物治疗的效果,加快很多患者的康复,并降低医疗费用。
基金This work was supported by the National Natural Science Fund for Excellent Young Scientists Fund Program(Overseas)to Y.Z.,the National Key Research and Development Program of China(grant 2019YFA0906200)the Agricultural Science and Technology Innovation Program(CAAS-ZDRW202101)+1 种基金the Shenzhen Science and Technology Program(grant KQTD2016113010482651)the BMBF-funded de.
文摘Grapevine is one of the most economically important crops worldwide.However,the previous versions of the grapevine reference genome tipically consist of thousands of fragments with missing centromeres and telomeres,limiting the accessibility of the repetitive sequences,the centromeric and telomeric regions,and the study of inheritance of important agronomic traits in these regions.Here,we assembled a telomere-to-telomere(T2T)gap-free reference genome for the cultivar PN40024 using PacBio HiFi long reads.The T2T reference genome(PN_T2T)is 69 Mb longer with 9018 more genes identified than the 12X.v0 version.We annotated 67%repetitive sequences,19 centromeres and 36 telomeres,and incorporated gene annotations of previous versions into the PN_T2T assembly.We detected a total of 377 gene clusters,which showed associations with complex traits,such as aroma and disease resistance.Even though PN40024 derives from nine generations of selfing,we still found nine genomic hotspots of heterozygous sites associated with biological processes,such as the oxidation–reduction process and protein phosphorylation.The fully annotated complete reference genome therefore constitutes an important resource for grapevine genetic studies and breeding programs.
基金Deutsche Forschungsgemeinschaft(415832635)H2020 Marie Sk?odowska-Curie Actions(752080)Bundesministerium für Bildung und Forschung(01IS18041C)。
文摘Super-resolution structured illumination microscopy(SR-SIM) provides an up to twofold enhanced spatial resolution of fluorescently labeled samples. The reconstruction of high-quality SR-SIM images critically depends on patterned illumination with high modulation contrast. Noisy raw image data(e.g., as a result of low excitation power or low exposure time), result in reconstruction artifacts. Here, we demonstrate deep-learning based SR-SIM image denoising that results in high-quality reconstructed images. A residual encoding–decoding convolutional neural network(RED-Net) was used to successfully denoise computationally reconstructed noisy SR-SIM images.We also demonstrate the end-to-end deep-learning based denoising and reconstruction of raw SIM images into high-resolution SR-SIM images. Both image reconstruction methods prove to be very robust against image reconstruction artifacts and generalize very well across various noise levels. The combination of computational image reconstruction and subsequent denoising via RED-Net shows very robust performance during inference after training even if the microscope settings change.
文摘N^6-methyladenosine(m^6A)emerges as an important modification in eukaryotic mRNAs.m^6A has first been reported in 1974,and its functional significance in mammalian gene regulation and importance for proper development have been well established.An arsenal of writer,eraser,and reader proteins accomplish deposition,removal,and interpretation of the m^6A mark,resulting in dynamic function.This led to the concept of an epitranscriptome,the compendium of RNA species with chemical modification ofthe nucleobases in the cell,in analogy to the epigenome.While m^6A has long been known to also exist in plant mRNAs,proteins involved in m^6A metabolism have only recently been detected by mutant analysis,homology search,and mRNA interactome capture in the reference plant Arabidopsis thaliana.Dysregulation ofthe m^6A modification causes severe developmental abnormalities of leaves and roots and altered timing of reproductive development.Furthermore,m^6A modification affects viral infection.Here,we discuss recent progress in identifying m^6A sites transcriptome-wide,in identifying the molecular players involved in writing,removing,and reading the mark,and in assigning functions to this RNA modification in 4.thaliana.We highlight similarities and differences to m^6A modification in mammals and provide an outlook on important questions that remain to be addressed.
文摘The stress-associated protein SAP12 belongs to the stress-associated protein （SAP） family with 14 members in Arabidopsis thaliana. SAP12 contains two AN1 zinc fingers and was identified in diagonal 2D redox SDS-PAGE as a protein undergoing major redox-dependent conformational changes. Its transcript was strongly induced under cold and salt stress in a time-dependent manner similar to SAP10, with high levels after 6 h and decreasing levels after 24 and 48 h. The tran- script regulation resembled those of the stress marker peroxiredoxin PrxllD at 24 and 48 h. Recombinant SAP12 protein showed redox-dependent changes in quaternary structure as visualized by altered electrophoretic mobility in non-reducing SDS polyacrylamide gel electrophoresis. The oxidized oligomer was reduced by high dithiothreitol concentrations, and also by E. coli thioredoxin TrxA with low dithiothreitol （DTF） concentrations or NADPH plus NADPH-dependent thioredoxin reductase. From Western blots, the SAP12 protein amount was estimated to be in the range of 0.5 ngμg^-1 leaf protein. SAP12 protein decreased under salt and cold stress. These data suggest a redox state-linked function of SAP12 in plant cells particularly under cold and salt stress.
基金Sondernforschungsbereich(SFB)701 of the German Research Council and National Natural Science Foundation of China(Grant Nos.11271011 and 11171347)
文摘Let G =(V,E) be a locally finite graph,whose measure μ(x) has positive lower bound,and A be the usual graph Laplacian.Applying the mountain-pass theorem due to Ambrosetti and Rabinowitz(1973),we establish existence results for some nonlinear equations,namely △u+hu=f(x,u),x∈V.In particular,we prove that if h and f satisfy certain assumptions,then the above-mentioned equation has strictly positive solutions.Also,we consider existence of positive solutions of the perturbed equation △u+hu=f(x,u)+∈g.Similar problems have been extensively studied on the Euclidean space as well as on Riemannian manifolds.
基金financially supported by the National Natural Science Foundation of China(Nos.12004179,U1832191,51801102,52271180,52001167 and 52101236)Guangdong-Hong Kong-Macao Joint Laboratory for Neutron Scattering Science and Technology+1 种基金the Fundamental Research Funds for the Central Universities(No.30922010802)the Sino-German Mobility Program from the Sino-German Center for Research Promotion(SGC)(No.M-0447)。
文摘The development of zero and negative therma expansion(i.e.,ZTE and NTE)materials is of crucial importance to the control of undesirable thermal expansion for high-precision devices.In the present work,ZTE and NTE were obtained in directionally-solidified Mn_(x)Fe_(5-x)Si_(3)alloys with a strong<001>texture,in striking contrast to positive thermal expansion in their isotropic counterparts Magnetometry and in-situ X-ray diffraction(XRD)measurements were performed to uncover the origin of the anomalous thermal expansion.Magnetic measurements indicate a strong easy-plane magnetocrystalline anisotropy in the textured samples,where the magnetic moments are aligned within the ab plane of the hexagonal structure Temperature-dependent XRD on the x=1 sample reveals a ZTE character in the ab plane that is coupled to a ferromagnetic transition.As a result,the macroscopic ZTE(~0.22×10^(-6)K^(-1))in the x=1 sample can be attributed to the microscopic magneto volume effect within the ab plane,which is realized by the introduction of the<001>-textured microstructure.Besides,the competition between antiferromagnetic and ferromagnetic exchange coupling leads to NTE in textured x=1.5 and 2 samples.Additionally,textured x=1 sample displays enhanced magnetocaloric properties as compared to the conventional counterparts with randomly-oriented grains.Consequently this work demonstrates a new strategy toward the exploration of anomalous thermal expansion properties as well as the enhancement of magnetocaloric properties for materials with a strong magnetocrystalline anisotropy.
基金This study was funded by a“Bielefeld Young Researchers'Fund"grant awarded by Bielefeld University(Germany)to I.D.M.under the code BYRF2021-DamasMoreira.
文摘Urbanization occurs at a global scale,imposing dramatic and abrupt environmental changes that lead to biodiversity loss.Yet,some animal species can handle these changes,and thrive in such artifcial environments.One possible explanation is that urban individuals are equipped with better cognitive abilities,but most studies have focused on birds and mammals and yielded varied results.Reptiles have received much less attention,despite some lizard species being common city dwellers.The Italian wall lizard,Podarcis siculus,and the common wall lizard,Podarcis muralis,are two successful lizards in anthropogenic habitats that thrive in urban locations.To test for differences in a cognitive skill between urban and semi-natural environments,we investigated inhibitory control through a detour task in syntopic populations of the two species,across 249 lizards that were tested in partially artifcial feld settings.Sophisticated inhibitory control is considered essential for higher degrees of cognitive fexibility and other higher-level cognitive abilities.In this task,we confronted lizards with a transparent barrier,separating them from a desired shelter area that they could only reach by controlling their impulse to go straight and instead detour the barrier.We found no differences between lizards in urban and semi-natural environments,nor between species,but females overall performed better than males.Moreover,48%of the lizards in our study did not perform a correct trial in any of the 5 trials,hinting at the diffculty of the task for these species.This study is among the frst to address lizard cognition,through their inhibitory control,as a potential explanation for success in cities and highlights one should be careful with assuming that urban animals generally have enhanced cognitive performance,as it might be taxa,task,or condition dependent.
基金This work was partly supported by the National Key R&D Program of China(No.2022YFF1202903)National Natural Science Foundation of China(Nos.62122035 and 62206122)。
文摘The recent rapid development of deep learning has laid a milestone in industrial image anomaly detection(IAD).In this pa-per,we provide a comprehensive review of deep learning-based image anomaly detection techniques,from the perspectives of neural net-work architectures,levels of supervision,loss functions,metrics and datasets.In addition,we extract the promising setting from indus-trial manufacturing and review the current IAD approaches under our proposed setting.Moreover,we highlight several opening chal-lenges for image anomaly detection.The merits and downsides of representative network architectures under varying supervision are discussed.Finally,we summarize the research findings and point out future research directions.More resources are available at https://github.com/M-3LAB/awesome-industrial-anomaly-detection.
基金supported by grants from National Natural Science Foundation of China(NSFC-32000208 and NSFC-32070769)National Key R&D Program of China(2023YFD1401100)+1 种基金China Postdoctoral Science Foundation funded project(2020M672475)the Science and Technology Innovation Program of Hunan Province(Nonos.2021JJ10015,2021JJ40060,2023ZJ1080,and 2021JJ40056).
文摘Changes in ambient temperature profoundly affect plant growth and performance.Therefore,the molecu-larbasis of plant acclimation to temperature fluctuation is of great interest.In this study,we discovered that GLYCINE-RICH RNA-BINDING PROTEIN 7(GRP7)contributes to cold and heat tolerance in Arabidopsis thaliana.We found that exposure to a warm temperature rapidly induces GRP7 condensates in planta,which can be reversed by transfer to a lower temperature.Cell biology and biochemical assays revealed that GRP7 undergoes liquid-liquid phase separation(LLPS)in vivo and in vitro.LLPS of GRP7 in the cyto-plasm contributes to the formation of stress granules that recruit RNA,along with the translation machinery component eukaryotic initiation factor 4E1(elF4E1)and the mRNA chaperones COLD SHOCK PROTEIN 1(CSP1)and CSP3,to inhibit translation.Moreover,natural variations in GRP7 affecting the residue phos-phorylated by the receptorkinase FERONIA alter its capacity to undergo LLPS and correlate with the adap-tation of some Arabidopsis accessions to a widertemperature range.Taken together,ourfindings illustrate the role of translational control mediated by GRP7 LLPS to confer plants with temperature resilience.
基金supported in part by the National Natural Science Foundation of China (62136003,62302147,62103150,62006053,and 62306097)in part by the China Postdoctoral Science Foundation (2021M691012)+1 种基金in part by the Natural Science Foundation of Guangdong Province (2022A1515010443)in part by the National Research,Development and Innovation Fund of Hungary under the Establishment of Competence Centers,Development of Research Infrastructure Programme funding scheme (2019-1.3.1-KK-2019-00011).
文摘With the development of edge devices and cloud computing,the question of how to accomplish machine learning and optimization tasks in a privacy-preserving and secure way has attracted increased attention over the past decade.As a privacy-preserving distributed machine learning method,federated learning(FL)has become popular in the last few years.However,the data privacy issue also occurs when solving optimization problems,which has received little attention so far.This survey paper is concerned with privacy-preserving optimization,with a focus on privacy-preserving data-driven evolutionary optimization.It aims to provide a roadmap from secure privacy-preserving learning to secure privacy-preserving optimization by summarizing security mechanisms and privacy-preserving approaches that can be employed in machine learning and optimization.We provide a formal definition of security and privacy in learning,followed by a comprehensive review of FL schemes and cryptographic privacy-preserving techniques.Then,we present ideas on the emerging area of privacy-preserving optimization,ranging from privacy-preserving distributed optimization to privacy-preserving evolutionary optimization and privacy-preserving Bayesian optimization(BO).We further provide a thorough security analysis of BO and evolutionary optimization methods from the perspective of inferring attacks and active attacks.On the basis of the above,an in-depth discussion is given to analyze what FL and distributed optimization strategies can be used for the design of federated optimization and what additional requirements are needed for achieving these strategies.Finally,we conclude the survey by outlining open questions and remaining challenges in federated data-driven optimization.We hope this survey can provide insights into the relationship between FL and federated optimization and will promote research interest in secure federated optimization.
基金supported by the Germany/Hong Kong Joint Research Scheme sponsored by the Research Grants Council of Hong Kongthe Germany Academic Exchange Service of Germany(G-HKU708/14,DAAD-57138104)+5 种基金the European Union’s Horizon 2020 research and innovation program under the Marie Sklodowska-Curie Grant Agreement No.766181,project“DeLIVER”the Research Grants Council of the Hong Kong Special Administrative Region,China(HKU 17205215,CityU T42-103/16-N,EHKU701/17,and HKU C7047-16G)the National Natural Science Foundation of China(N_HKU712/16)Innovation and Technology Fund(GHP/050/14GD)support for the Article Processing Charge by the Deutsche Forschungsgemeinschaftthe Open Access Publication Fund of Bielefeld University.
文摘Coherent Raman scattering(CRS)microscopy is widely recognized as a powerful tool for tackling biomedical problems based on its chemically specific label-free contrast,high spatial and spectral resolution,and high sensitivity.However,the clinical translation of CRS imaging technologies has long been hindered by traditional solid-state lasers with environmentally sensitive operations and large footprints.Ultrafast fibre lasers can potentially overcome these shortcomings but have not yet been fully exploited for CRS imaging,as previous implementations have suffered from high intensity noise,a narrow tuning range and low power,resulting in low image qualities and slow imaging speeds.Here,we present a novel high-power self-synchronized two-colour pulsed fibre laser that achieves excellent performance in terms of intensity stability(improved by 50 dB),timing jitter(24.3 fs),average power fluctuation(<0.5%),modulation depth(>20 dB)and pulse width variation(<1.8%)over an extended wavenumber range(2700-3550 cm^(−1)).The versatility of the laser source enables,for the first time,high-contrast,fast CRS imaging without complicated noise reduction via balanced detection schemes.These capabilities are demonstrated in this work by imaging a wide range of species such as living human cells and mouse arterial tissues and performing multimodal nonlinear imaging of mouse tail,kidney and brain tissue sections by utilizing second-harmonic generation and twophoton excited fluorescence,which provides multiple optical contrast mechanisms simultaneously and maximizes the gathered information content for biological visualization and medical diagnosis.This work also establishes a general scenario for remodelling existing lasers into synchronized two-colour lasers and thus promotes a wider popularization and application of CRS imaging technologies.
文摘In plants, the highly abundant 2-cysteine peroxiredoxin （2-CysPrx） is associated with the chloroplast and involved in protecting photosynthesis. This work addresses the multiple interactions of the 2-CysPrx in the chloroplast, which depend on its redox state. Transcript co-regulation analysis showed a strong linkage to the peptidyl-prolyl-cis/trans isomerase Cyclophilin 20-3 （Cyp20-3） and other components of the photosynthetic apparatus. Co-expression in protoplasts and quantification of fluorescence resonance energy transfer （FRET） efficiency in vivo confirmed protein interactions of 2-CysPrx with Cyp20-3 as well as NADPH-dependent thioredoxin reductase C （NTRC）, while thioredoxin x （Trx-x） did not form complexes that could enable FRET. Likewise, changes in FRET of fluorescently labeled 2-CysPrx in vitro and in vivo proved redox dependent dynamics of 2-CysPrx. Addition of Cyp20-3 to an in vitro peroxidase assay with 2-CysPrx had no significant effect on peroxide reduction. Also, in the presence of NTRC, addition of Cyp20-3 did not further enhance peroxide reduction. In addition, 2-CysPrx functioned as chaperone and inhibited aggregation of citrate synthase during heat treatment. This activity was partly inhibited by Cyp20-3. As a new interaction partner of decameric 2-CysPrx, photosystem Ⅱ could be identified after chloroplast fractionation and in pull-down assays after reconstitution. In summary, the data indicate a dynamic function of plant 2-CysPrx as redox sensor, chaperone, and regulator in the chloroplast with diverse functions beyond its role as thiol peroxidase.
文摘Cluster of differentiation 74(CD74),also called as major histocompatibility complex class Ⅱ(MHCⅡ)invariant chain,is involved in trafficking MHCⅡ cell surface molecules on antigen-presenting cells and has been implicated in many signaling pathways.For example,the interaction between CD74 and macrophage migration inhibitory factor cyto kine(MIF) leads to the activation of a plethora of pathways such as extracellular regulated protein kinases,phosphoinositide 3-kinase.
基金the National Natural Science Foundation of China(62076225,62073300)the Natural Science Foundation for Distinguished Young Scholars of Hubei(2019CFA081)。
文摘Solving constrained multi-objective optimization problems with evolutionary algorithms has attracted considerable attention.Various constrained multi-objective optimization evolutionary algorithms(CMOEAs)have been developed with the use of different algorithmic strategies,evolutionary operators,and constraint-handling techniques.The performance of CMOEAs may be heavily dependent on the operators used,however,it is usually difficult to select suitable operators for the problem at hand.Hence,improving operator selection is promising and necessary for CMOEAs.This work proposes an online operator selection framework assisted by Deep Reinforcement Learning.The dynamics of the population,including convergence,diversity,and feasibility,are regarded as the state;the candidate operators are considered as actions;and the improvement of the population state is treated as the reward.By using a Q-network to learn a policy to estimate the Q-values of all actions,the proposed approach can adaptively select an operator that maximizes the improvement of the population according to the current state and thereby improve the algorithmic performance.The framework is embedded into four popular CMOEAs and assessed on 42 benchmark problems.The experimental results reveal that the proposed Deep Reinforcement Learning-assisted operator selection significantly improves the performance of these CMOEAs and the resulting algorithm obtains better versatility compared to nine state-of-the-art CMOEAs.
文摘Mucopolysaccharidoses(MPS)are a group of rare inborn errors of metabolism caused by defective lysosomal enzymes which prevent cells from degrading and recycling certain carbohydrates and fats,resulting in the storage of glycosaminoglycans in cells throughout the body.This leads to multisystem abnormalities involving bone,connective tissues,brain,blood,spinal cord,skin,and other tissues.
基金supported in part by the National Key Research and Development Program of China(2018AAA0100100)the National Natural Science Foundation of China(61906001,62136008,U21A20512)+1 种基金the Key Program of Natural Science Project of Educational Commission of Anhui Province(KJ2020A0036)Alexander von Humboldt Professorship for Artificial Intelligence Funded by the Federal Ministry of Education and Research,Germany。
文摘Large-scale multi-objective optimization problems(LSMOPs)pose challenges to existing optimizers since a set of well-converged and diverse solutions should be found in huge search spaces.While evolutionary algorithms are good at solving small-scale multi-objective optimization problems,they are criticized for low efficiency in converging to the optimums of LSMOPs.By contrast,mathematical programming methods offer fast convergence speed on large-scale single-objective optimization problems,but they have difficulties in finding diverse solutions for LSMOPs.Currently,how to integrate evolutionary algorithms with mathematical programming methods to solve LSMOPs remains unexplored.In this paper,a hybrid algorithm is tailored for LSMOPs by coupling differential evolution and a conjugate gradient method.On the one hand,conjugate gradients and differential evolution are used to update different decision variables of a set of solutions,where the former drives the solutions to quickly converge towards the Pareto front and the latter promotes the diversity of the solutions to cover the whole Pareto front.On the other hand,objective decomposition strategy of evolutionary multi-objective optimization is used to differentiate the conjugate gradients of solutions,and the line search strategy of mathematical programming is used to ensure the higher quality of each offspring than its parent.In comparison with state-of-the-art evolutionary algorithms,mathematical programming methods,and hybrid algorithms,the proposed algorithm exhibits better convergence and diversity performance on a variety of benchmark and real-world LSMOPs.
