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Pangolin scales as adaptations for innate immunity against pathogens. 穿山甲的鳞片是对病原体先天免疫的适应。
IF 4.4 1区 生物学 Q1 BIOLOGY Pub Date : 2024-10-14 DOI: 10.1186/s12915-024-02034-5
Xuechen Tian, Li Chen, Jinfeng Zhou, Enbo Wang, Mu Wang, Nicholas Jakubovics, Jing Li, Kunping Song, King Tong Lau, Klaus-Peter Koepfli, Siyuan Zhang, Geok Yuan Annie Tan, Yixin Yang, Siew Woh Choo

Background: Pangolins are the only mammals that have overlapping scales covering most of their bodies, and they play a crucial role in the ecosystem, biological research, and human health and disease. Previous studies indicated pangolin scale might provide an important mechanical defense to themselves. The origin and exact functions of this unique trait remain a mystery. Using a multi-omics analysis approach, we report a novel functional explanation for how mammalian scales can provide host-pathogen defense.

Results: Our data suggest that pangolin scales have a sophisticated structure that could potentially trap pathogens. We identified numerous proteins and metabolites exhibiting antimicrobial activity, which could suggest a role for scales in pathogen defense. Notably, we found evidence suggesting the presence of exosomes derived from diverse cellular origins, including mesenchymal stem cells, immune cells, and keratinocytes. This observation suggests a complex interplay where various cell types may contribute to the release of exosomes and antimicrobial compounds at the interface between scales and viable tissue. These findings indicate that pangolin scales may serve as a multifaceted defense system, potentially contributing to innate immunity. Comparisons with human nail and hair revealed pangolin-specific proteins that were enriched in functions relating to sensing, immune responses, neutrophil degranulation, and stress responses. We demonstrated the antimicrobial activity of key pangolin scale components on pathogenic bacteria by antimicrobial assays.

Conclusions: This study identifies a potential role of pangolin scales and implicates scales, as possible determinants of pathogen defense due to their structure and contents. We indicate for the first time the presence of exosomes in pangolin scales and propose the new functions of scales and their mechanisms. This new mechanism could have implications for multiple fields, including providing interesting new research directions and important insights that can be useful for synthesizing and implementing new biomimetic antimicrobial approaches.

背景:穿山甲是唯一身体大部分覆盖有重叠鳞片的哺乳动物,在生态系统、生物研究、人类健康和疾病方面发挥着重要作用。以前的研究表明,穿山甲的鳞片可能为其自身提供了重要的机械防御功能。这种独特特征的起源和确切功能仍然是一个谜。利用多组学分析方法,我们报告了哺乳动物鳞片如何提供宿主-病原体防御的新功能解释:我们的数据表明,穿山甲的鳞片具有复杂的结构,有可能捕获病原体。我们发现了许多具有抗菌活性的蛋白质和代谢物,这可能表明鳞片在病原体防御中的作用。值得注意的是,我们发现有证据表明存在来自不同细胞来源的外泌体,包括间充质干细胞、免疫细胞和角质细胞。这一观察结果表明,在鳞片和有活力组织之间的界面上,各种细胞类型可能有助于外泌体和抗菌化合物的释放,从而产生了复杂的相互作用。这些研究结果表明,穿山甲的鳞片可能是一种多方面的防御系统,有可能对先天性免疫做出贡献。通过与人类指甲和毛发的比较,我们发现穿山甲的特异性蛋白质富含与传感、免疫反应、中性粒细胞脱颗粒和应激反应有关的功能。我们通过抗菌试验证明了穿山甲鳞片的主要成分对病原菌的抗菌活性:本研究确定了穿山甲鳞片的潜在作用,并认为鳞片的结构和内容可能决定了病原体的防御能力。我们首次发现穿山甲鳞片中存在外泌体,并提出了鳞片的新功能及其机制。这一新机制可能会对多个领域产生影响,包括提供有趣的新研究方向和重要见解,这些见解可能有助于合成和实施新的生物仿生抗菌方法。
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引用次数: 0
Juvenile hormone signaling is indispensable for late embryogenesis in ametabolous and hemimetabolous insects. 幼年激素信号对于双代谢昆虫和半双代谢昆虫的后期胚胎发生是不可或缺的。
IF 4.4 1区 生物学 Q1 BIOLOGY Pub Date : 2024-10-11 DOI: 10.1186/s12915-024-02029-2
Ya-Nan Lv, Mei Zeng, Zi-Yu Yan, Pei-Yan Zhang, Ning Ban, Dong-Wei Yuan, Sheng Li, Yun-Xia Luan, Yu Bai

Background: Juvenile hormone (JH) is an insect-exclusive hormone involved in regulating diverse aspects of insect physiology, and the evolution of its diverse function is widely interesting. Studying embryogenesis in basal wingless insects is important to understand the functional evolution of JH; however, experimental studies in this regard are scarce. In this study, we conducted CRISPR/Cas9-mediated knockout (KO) of genes involved in JH biosynthesis and signaling cascades in the ametabolous firebrat, Thermobia domestica. Additionally, we investigated whether the primitive action of JH is conserved in the hemimetabolous cricket, Gryllus bimaculatus.

Results: We observed that KO of JHAMT, CYP15A1, Met, and Kr-h1 resulted in embryonic lethality in T. domestica. Deprivation of JH or JH signaling arrested the progression of extraembryonic fluid resorption after dorsal closure and hatching, which is consistent with the gene expression pattern showing high Kr-h1 expression in the late embryos of T. domestica. The embryos deficient in JH signaling displayed wrinkled and weak legs. Comparative transcriptome analysis revealed that JH signaling promotes embryonic leg maturation through inducing energy supply and muscle activity, as validated by transmission electron microscopy (TEM). In addition, JH signaling exhibited similar embryonic effects in G. bimaculatus.

Conclusions: This study reveals the indispensable role of JH signaling in facilitating the maturation of terminal tissues during late embryogenesis, as demonstrated by the regulation of leg development, in ametabolous and hemimetabolous insects. These findings further indicate that the embryonic functions of JH evolved earlier than its anti-metamorphic functions during postembryonic development.

背景:幼年激素(JH)是一种昆虫独有的激素,参与调节昆虫生理的各个方面,其多样化功能的进化具有广泛的意义。研究基性无翅昆虫的胚胎发生对了解 JH 的功能进化非常重要;然而,这方面的实验研究却很少。在本研究中,我们在CRISPR/Cas9介导下敲除了参与双代谢萤火虫(Thermobia domestica)JH生物合成和信号级联的基因。此外,我们还研究了 JH 的原始作用在半代谢蟋蟀 Gryllus bimaculatus 中是否保持不变:结果:我们观察到,KO JHAMT、CYP15A1、Met 和 Kr-h1 会导致蟋蟀胚胎死亡。JH或JH信号的缺失会阻止胚胎背闭合和孵化后胚外液的吸收,这与Kr-h1在驯鹿晚期胚胎中高表达的基因表达模式是一致的。缺乏 JH 信号传导的胚胎腿部起皱且无力。比较转录组分析表明,JH 信号通过诱导能量供应和肌肉活动促进胚胎腿的成熟,透射电子显微镜(TEM)验证了这一点。此外,JH 信号在 G. bimaculatus 中也表现出类似的胚胎效应:本研究揭示了 JH 信号在胚胎后期发育过程中促进末端组织成熟过程中不可或缺的作用,这一点在双代谢和半代谢昆虫的腿部发育调控中得到了证明。这些发现进一步表明,JH的胚胎功能早于其在胚后发育过程中的抗变态功能。
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引用次数: 0
Ecological adaptations of amphibians to environmental changes along an altitudinal gradient (Case Study: Bufo gargarizans) from phenotypic and genetic perspectives. 从表型和遗传角度看两栖动物对海拔梯度环境变化的生态适应性(案例研究:Bufo gargarizans)。
IF 4.4 1区 生物学 Q1 BIOLOGY Pub Date : 2024-10-10 DOI: 10.1186/s12915-024-02033-6
Yonggang Niu, Xuejing Zhang, Haiying Zhang, Shengkang Men, Tisen Xu, Li Ding, Xiangyong Li, Lei Wang, Huisong Wang, Kenneth B Storey, Qiang Chen

Background: Organisms have evolved a range of phenotypic and genetic adaptations to live in different environments along an altitudinal gradient. Herein, we studied the widely distributed Chinese toad, Bufo gargarizans, as a model and used an integrated phenotype-genotype approach to assess adaptations to different altitudinal environments.

Results: Comparison of populations from four altitudes (50 m, 1200 m, 2300 m, and 3400 m) showed more effective defenses among high-altitude toads. These included thickened epidermis, more epidermal capillaries and granular glands, greater gland size in skin, and higher antioxidant enzyme activities in plasma. High-altitude toads also showed increased erythrocytes and hematocrit and elevated hemoglobin concentration, potentially improving oxygen delivery. Elevated altitude led to a metabolic shift from aerobic to anaerobic metabolism, and high-altitude populations favored carbohydrates over fatty acids to fuel for energy metabolism. Differentially expressed genes were associated with adaptive phenotypic changes. For instance, expression of genes associated with fatty acid metabolism showed greater suppression at high altitude (3400 m), consistent with decreased flux of β-hydroxybutyric acid and lower free fatty acids levels. Moreover, down-regulation of genes involved in carbon metabolism processes at high altitude (3400 m) were coincident with reduced TCA cycle flux. These results suggest that high-altitude toads adopt a metabolic suppression strategy for survival under harsh environmental conditions. Moreover, the hypoxia-inducible factor signaling cascade was activated at high altitude.

Conclusions: Collectively, these results advance our comprehension of adaptation to high-altitude environments by revealing physiological and genetic mechanisms at work in Chinese toads living along altitudinal gradients.

背景:生物进化出一系列表型和遗传适应性,以适应沿海拔梯度的不同环境。在此,我们以分布广泛的中华蟾蜍为模型,采用表型-基因型综合方法评估其对不同海拔环境的适应性:结果:对来自四种海拔高度(50米、1200米、2300米和3400米)的种群进行比较后发现,高海拔蟾蜍的防御能力更强。这包括表皮增厚、表皮毛细血管和颗粒状腺体增多、皮肤腺体增大以及血浆中抗氧化酶活性提高。高海拔蟾蜍的红细胞和血细胞比容也有所增加,血红蛋白浓度升高,这可能会改善氧气的输送。海拔升高导致新陈代谢从有氧代谢转向无氧代谢,高海拔种群在能量代谢过程中更倾向于以碳水化合物而不是脂肪酸作为燃料。差异表达的基因与适应性表型变化有关。例如,与脂肪酸代谢相关的基因表达在高海拔地区(3400 米)受到更大抑制,这与β-羟丁酸通量减少和游离脂肪酸水平降低相一致。此外,高海拔地区(3400 米)碳代谢过程相关基因的下调与 TCA 循环通量的减少相吻合。这些结果表明,高海拔地区的蟾蜍为了在恶劣的环境条件下生存,采取了抑制代谢的策略。此外,低氧诱导因子信号级联在高海拔地区被激活:总之,这些结果揭示了沿海拔梯度生活的中华蟾蜍的生理和遗传机制,从而加深了我们对高海拔环境适应性的理解。
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引用次数: 0
Rapid evolution of mitochondrion-related genes in haplodiploid arthropods. 单倍体节肢动物中线粒体相关基因的快速进化。
IF 4.4 1区 生物学 Q1 BIOLOGY Pub Date : 2024-10-10 DOI: 10.1186/s12915-024-02027-4
Yiyuan Li, Gregg W C Thomas, Stephen Richards, Robert M Waterhouse, Xin Zhou, Michael E Pfrender

Background: Mitochondrial genes and nuclear genes cooperate closely to maintain the functions of mitochondria, especially in the oxidative phosphorylation (OXPHOS) pathway. However, mitochondrial genes among arthropod lineages have dramatic evolutionary rate differences. Haplodiploid arthropods often show fast-evolving mitochondrial genes. One hypothesis predicts that the small effective population size of haplodiploid species could enhance the effect of genetic drift leading to higher substitution rates in mitochondrial and nuclear genes. Alternatively, positive selection or compensatory changes in nuclear OXPHOS genes could lead to the fast-evolving mitochondrial genes. However, due to the limited number of arthropod genomes, the rates of evolution for nuclear genes in haplodiploid species, besides hymenopterans, are largely unknown. To test these hypotheses, we used data from 76 arthropod genomes, including 5 independently evolved haplodiploid lineages, to estimate the evolutionary rates and patterns of gene family turnover of mitochondrial and nuclear genes.

Results: We show that five haplodiploid lineages tested here have fast-evolving mitochondrial genes and fast-evolving nuclear genes related to mitochondrial functions, while nuclear genes not related to mitochondrion showed no significant evolutionary rate differences. Among hymenopterans, bees and ants show faster rates of molecular evolution in mitochondrial genes and mitochondrion-related nuclear genes than sawflies and wasps. With genome data, we also find gene family expansions and contractions in mitochondrion-related genes of bees and ants.

Conclusions: Our results reject the small population size hypothesis in haplodiploid species. A combination of positive selection and compensatory changes could lead to the observed patterns in haplodiploid species. The elevated evolutionary rates in OXPHOS complex 2 genes of bees and ants suggest a unique evolutionary history of social hymenopterans.

背景:线粒体基因与核基因密切合作,共同维持线粒体的功能,尤其是氧化磷酸化(OXPHOS)途径的功能。然而,节肢动物各系之间的线粒体基因在进化速度上存在巨大差异。单倍体节肢动物的线粒体基因通常进化迅速。一种假设认为,单倍体物种的有效种群规模较小,这可能会增强遗传漂变的效果,导致线粒体基因和核基因的替代率升高。另外,核 OXPHOS 基因的正向选择或补偿性变化也可能导致线粒体基因的快速进化。然而,由于节肢动物基因组的数量有限,除膜翅目动物外,单倍体物种中核基因的进化速度在很大程度上是未知的。为了验证这些假设,我们使用了来自76个节肢动物基因组的数据,其中包括5个独立进化的单倍体系,来估计线粒体基因和核基因的进化速度和基因家族更替模式:结果表明,本文测试的5个单倍体系的线粒体基因进化较快,与线粒体功能相关的核基因进化较快,而与线粒体无关的核基因在进化速度上没有明显差异。在膜翅目昆虫中,蜜蜂和蚂蚁的线粒体基因以及与线粒体相关的核基因的分子进化速度快于锯蝇和黄蜂。通过基因组数据,我们还发现蜜蜂和蚂蚁的线粒体相关基因的家族扩张和收缩:我们的研究结果否定了单倍体物种种群规模较小的假说。正向选择和补偿性变化的结合可能导致在单倍体物种中观察到的模式。蜜蜂和蚂蚁OXPHOS复合体2基因进化率的提高表明社会性膜翅目昆虫具有独特的进化历史。
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引用次数: 0
Author Correction: Identification and characterization of a set of conserved and new regulators of cytoskeletal organization, cell morphology and migration. 作者更正:细胞骨架组织、细胞形态和迁移的一组保守调节因子和新调节因子的鉴定与表征。
IF 4.4 1区 生物学 Q1 BIOLOGY Pub Date : 2024-10-10 DOI: 10.1186/s12915-024-02036-3
Siau Wei Bai, Maria Teresa Herrera-Abreu, Jennifer L Rohn, Victor Racine, Virginia Tajadura, Narendra Suryavanshi, Stephanie Bechtel, Stefan Wiemann, Buzz Baum, Anne J Ridley
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引用次数: 0
The evolution of ectomycorrhizal symbiosis and host-plant switches are the main drivers for diversification of Amanitaceae (Agaricales, Basidiomycota). 外生菌根共生的进化和宿主-植物的转换是天南星科(姬松茸属,担子菌纲)多样化的主要驱动力。
IF 4.4 1区 生物学 Q1 BIOLOGY Pub Date : 2024-10-10 DOI: 10.1186/s12915-024-02031-8
Qing Cai, Jean Evans I Codjia, Bart Buyck, Yang-Yang Cui, Martin Ryberg, Nourou S Yorou, Zhu L Yang

Background: Evolutionary radiation is widely recognized as a mode of species diversification, but the drivers of the rapid diversification of fungi remain largely unknown. Here, we used Amanitaceae, one of the most diverse families of macro-fungi, to investigate the mechanism underlying its diversification.

Results: The ancestral state of the nutritional modes was assessed based on phylogenies obtained from fragments of 36 single-copy genes and stable isotope analyses of carbon and nitrogen. Moreover, a number of time-, trait-, and paleotemperature-dependent models were employed to investigate if the acquisition of ectomycorrhizal (ECM) symbiosis and climate changes promoted the diversification of Amanitaceae. The results indicate that the evolution of ECM symbiosis has a single evolutionary origin in Amanitaceae. The earliest increase in diversification coincided with the acquisition of the ECM symbiosis with angiosperms in the middle Cretaceous. The recent explosive diversification was primarily triggered by the host-plant switches from angiosperms to the mixed forests dominated by Fagaceae, Salicaceae, and Pinaceae or to Pinaceae.

Conclusions: Our study provides a good example of integrating phylogeny, nutritional mode evolution, and ecological analyses for deciphering the mechanisms underlying fungal evolutionary diversification. This study also provides new insights into how the transition to ECM symbiosis has driven the diversification of fungi.

背景:进化辐射被广泛认为是物种多样化的一种模式,但真菌快速多样化的驱动因素在很大程度上仍然未知。在此,我们利用大型真菌中最多样化的科之一天南星科来研究其多样化的内在机制:结果:根据 36 个单拷贝基因片段的系统进化以及碳和氮的稳定同位素分析,评估了营养模式的祖先状态。此外,还采用了一些时间、性状和古温度依赖模型来研究外生菌根(ECM)共生的获得和气候变化是否促进了天南星科植物的多样化。结果表明,ECM共生的进化在天南星科植物中只有一个进化起源。在白垩纪中期,天南星科获得了与被子植物的ECM共生关系,这也是天南星科最早的多样化。最近的爆炸性多样化主要是由宿主植物从被子植物转向以椑科、水杨科和松科为主的混交林或松科植物引发的:我们的研究为综合系统发育、营养模式演化和生态学分析解密真菌进化多样化的机制提供了一个很好的范例。本研究还为了解向 ECM 共生过渡如何推动真菌的多样化提供了新的见解。
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引用次数: 0
TransCDR: a deep learning model for enhancing the generalizability of drug activity prediction through transfer learning and multimodal data fusion. TransCDR:通过迁移学习和多模态数据融合提高药物活性预测通用性的深度学习模型。
IF 4.4 1区 生物学 Q1 BIOLOGY Pub Date : 2024-10-09 DOI: 10.1186/s12915-024-02023-8
Xiaoqiong Xia, Chaoyu Zhu, Fan Zhong, Lei Liu

Background: Accurate and robust drug response prediction is of utmost importance in precision medicine. Although many models have been developed to utilize the representations of drugs and cancer cell lines for predicting cancer drug responses (CDR), their performances can be improved by addressing issues such as insufficient data modality, suboptimal fusion algorithms, and poor generalizability for novel drugs or cell lines.

Results: We introduce TransCDR, which uses transfer learning to learn drug representations and fuses multi-modality features of drugs and cell lines by a self-attention mechanism, to predict the IC50 values or sensitive states of drugs on cell lines. We are the first to systematically evaluate the generalization of the CDR prediction model to novel (i.e., never-before-seen) compound scaffolds and cell line clusters. TransCDR shows better generalizability than 8 state-of-the-art models. TransCDR outperforms its 5 variants that train drug encoders (i.e., RNN and AttentiveFP) from scratch under various scenarios. The most critical contributors among multiple drug notations and omics profiles are Extended Connectivity Fingerprint and genetic mutation. Additionally, the attention-based fusion module further enhances the predictive performance of TransCDR. TransCDR, trained on the GDSC dataset, demonstrates strong predictive performance on the external testing set CCLE. It is also utilized to predict missing CDRs on GDSC. Moreover, we investigate the biological mechanisms underlying drug response by classifying 7675 patients from TCGA into drug-sensitive or drug-resistant groups, followed by a Gene Set Enrichment Analysis.

Conclusions: TransCDR emerges as a potent tool with significant potential in drug response prediction.

背景:准确而稳健的药物反应预测在精准医疗中至关重要。尽管已经开发了许多模型来利用药物和癌细胞系的表征预测癌症药物反应(CDR),但通过解决数据模态不足、次优融合算法以及对新型药物或细胞系的普适性差等问题,这些模型的性能还可以得到改善:我们介绍了TransCDR,它利用迁移学习来学习药物表征,并通过自注意机制融合药物和细胞系的多模态特征,从而预测药物在细胞系上的IC50值或敏感状态。我们首次系统地评估了 CDR 预测模型对新型(即从未见过的)化合物支架和细胞系群的普适性。与 8 个最先进的模型相比,TransCDR 显示出更好的通用性。在各种情况下,TransCDR 都优于其 5 个从头开始训练药物编码器(即 RNN 和 AttentiveFP)的变体。在多种药物符号和 omics 资料中,最重要的贡献者是扩展连接指纹和基因突变。此外,基于注意力的融合模块进一步提高了 TransCDR 的预测性能。在 GDSC 数据集上训练的 TransCDR 在外部测试集 CCLE 上表现出很强的预测性能。它还被用于预测 GDSC 上缺失的 CDR。此外,我们还通过将来自 TCGA 的 7675 名患者分为药物敏感组和药物耐受组,然后进行基因组富集分析,研究了药物反应的生物机制:TransCDR是一种有效的工具,在药物反应预测方面具有巨大潜力。
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引用次数: 0
DrugReAlign: a multisource prompt framework for drug repurposing based on large language models. DrugReAlign:基于大型语言模型的药物再利用多源提示框架。
IF 4.4 1区 生物学 Q1 BIOLOGY Pub Date : 2024-10-08 DOI: 10.1186/s12915-024-02028-3
Jinhang Wei, Linlin Zhuo, Xiangzheng Fu, XiangXiang Zeng, Li Wang, Quan Zou, Dongsheng Cao

Drug repurposing is a promising approach in the field of drug discovery owing to its efficiency and cost-effectiveness. Most current drug repurposing models rely on specific datasets for training, which limits their predictive accuracy and scope. The number of both market-approved and experimental drugs is vast, forming an extensive molecular space. Due to limitations in parameter size and data volume, traditional drug-target interaction (DTI) prediction models struggle to generalize well within such a broad space. In contrast, large language models (LLMs), with their vast parameter sizes and extensive training data, demonstrate certain advantages in drug repurposing tasks. In our research, we introduce a novel drug repurposing framework, DrugReAlign, based on LLMs and multi-source prompt techniques, designed to fully exploit the potential of existing drugs efficiently. Leveraging LLMs, the DrugReAlign framework acquires general knowledge about targets and drugs from extensive human knowledge bases, overcoming the data availability limitations of traditional approaches. Furthermore, we collected target summaries and target-drug space interaction data from databases as multi-source prompts, substantially improving LLM performance in drug repurposing. We validated the efficiency and reliability of the proposed framework through molecular docking and DTI datasets. Significantly, our findings suggest a direct correlation between the accuracy of LLMs' target analysis and the quality of prediction outcomes. These findings signify that the proposed framework holds the promise of inaugurating a new paradigm in drug repurposing.

药物再利用因其高效性和成本效益而成为药物发现领域一种前景广阔的方法。目前大多数药物再利用模型都依赖于特定的数据集进行训练,这限制了其预测的准确性和范围。市场批准的药物和实验药物数量庞大,形成了一个广阔的分子空间。由于参数大小和数据量的限制,传统的药物-靶点相互作用(DTI)预测模型很难在如此广阔的空间内很好地泛化。相比之下,大语言模型(LLM)具有庞大的参数规模和大量的训练数据,在药物再利用任务中显示出一定的优势。在我们的研究中,我们介绍了一种基于 LLMs 和多源提示技术的新型药物再利用框架--DrugReAlign,旨在高效地充分挖掘现有药物的潜力。利用 LLMs,DrugReAlign 框架从广泛的人类知识库中获取有关靶点和药物的一般知识,克服了传统方法的数据可用性限制。此外,我们还从数据库中收集了靶点摘要和靶点-药物空间相互作用数据作为多源提示,大大提高了 LLM 在药物再利用中的性能。我们通过分子对接和 DTI 数据集验证了拟议框架的效率和可靠性。值得注意的是,我们的研究结果表明,LLM 目标分析的准确性与预测结果的质量直接相关。这些发现表明,所提出的框架有望开创药物再利用的新模式。
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引用次数: 0
Global analysis of neuropeptide receptor conservation across phylum Nematoda. 线虫纲神经肽受体保护的全球分析。
IF 4.4 1区 生物学 Q1 BIOLOGY Pub Date : 2024-10-08 DOI: 10.1186/s12915-024-02017-6
Luca Golinelli, Ellen Geens, Allister Irvine, Ciaran J McCoy, Elke Vandewyer, Louise E Atkinson, Angela Mousley, Liesbet Temmerman, Isabel Beets

Background: The phylum Nematoda is incredibly diverse and includes many parasites of humans, livestock, and plants. Peptide-activated G protein-coupled receptors (GPCRs) are central to the regulation of physiology and numerous behaviors, and they represent appealing pharmacological targets for parasite control. Efforts are ongoing to characterize the functions and define the ligands of nematode GPCRs, with already most peptide GPCRs known or predicted in Caenorhabditis elegans. However, comparative analyses of peptide GPCR conservation between C. elegans and other nematode species are limited, and many nematode GPCRs remain orphan. A phylum-wide perspective on peptide GPCR profiles will benefit functional and applied studies of nematode peptide GPCRs.

Results: We constructed a pan-phylum resource of C. elegans peptide GPCR orthologs in 125 nematode species using a semi-automated pipeline for analysis of predicted proteome datasets. The peptide GPCR profile varies between nematode species of different phylogenetic clades and multiple C. elegans peptide GPCRs have orthologs across the phylum Nematoda. We identified peptide ligands for two highly conserved orphan receptors, NPR-9 and NPR-16, that belong to the bilaterian galanin/allatostatin A (Gal/AstA) and somatostatin/allatostatin C (SST/AstC) receptor families. The AstA-like NLP-1 peptides activate NPR-9 in cultured cells and are cognate ligands of this receptor in vivo. In addition, we discovered an AstC-type peptide, NLP-99, that activates the AstC-type receptor NPR-16. In our pan-phylum resource, the phylum-wide representation of NPR-9 and NPR-16 resembles that of their cognate ligands more than those of allatostatin-like peptides that do not activate these receptors.

Conclusions: The repertoire of C. elegans peptide GPCR orthologs varies across phylogenetic clades and several peptide GPCRs show broad conservation in the phylum Nematoda. Our work functionally characterizes the conserved receptors NPR-9 and NPR-16 as the respective GPCRs for the AstA-like NLP-1 peptides and the AstC-related peptide NLP-99. NLP-1 and NLP-99 are widely conserved in nematodes and their representation matches that of their receptor in most species. These findings demonstrate the conservation of a functional Gal/AstA and SST/AstC signaling system in nematodes. Our dataset of C. elegans peptide GPCR orthologs also lays a foundation for further functional studies of peptide GPCRs in the widely diverse nematode phylum.

背景:线虫门种类繁多,包括许多寄生于人类、家畜和植物的寄生虫。肽激活的 G 蛋白偶联受体(GPCR)是调节生理机能和多种行为的核心,它们是控制寄生虫的诱人药理靶标。目前正在努力研究线虫 GPCR 的功能特征并确定其配体,在秀丽隐杆线虫中已知或预测的多肽 GPCR 已达数百种。然而,对 elegans 和其他线虫物种之间多肽 GPCR 保护情况的比较分析还很有限,许多线虫 GPCR 仍然是 "孤儿"。从整个动物门类的角度来研究多肽 GPCR 将有利于线虫多肽 GPCR 的功能和应用研究:结果:我们利用半自动流水线分析了预测的蛋白质组数据集,在 125 种线虫中构建了线虫多肽 GPCR 同源物的泛门资源。不同系统发育支系的线虫物种之间的多肽 GPCR 特征各不相同,线虫多肽 GPCR 在整个线虫纲中有多个直向同源物。我们发现了两种高度保守的孤儿受体 NPR-9 和 NPR-16 的多肽配体,它们属于双子叶动物的加拉宁/动情素 A(Gal/AstA)和体生长抑素/动情素 C(SST/AstC)受体家族。类似 AstA 的 NLP-1 肽能在培养细胞中激活 NPR-9,在体内也是该受体的同源配体。此外,我们还发现了一种 AstC 型多肽 NLP-99,它能激活 AstC 型受体 NPR-16。在我们的泛门资源中,NPR-9和NPR-16的全门代表性与其同源配体的代表性更相似,而与不激活这些受体的异磷脂素样肽的代表性更相似:结论:在不同的系统发育支系中,秀丽隐杆线虫肽GPCR直向同源物的种类各不相同,而在线虫门中,有几种肽GPCR表现出广泛的保守性。我们的工作从功能上确定了保守受体 NPR-9 和 NPR-16 的特征,它们分别是 AstA 样 NLP-1 肽和 AstC 相关肽 NLP-99 的 GPCR。NLP-1 和 NLP-99 在线虫中广泛保守,它们在大多数物种中的表现与其受体一致。这些发现证明了线虫中功能性 Gal/AstA 和 SST/AstC 信号系统的保守性。我们的线虫多肽 GPCR 同源物数据集还为进一步研究线虫门中多肽 GPCR 的功能奠定了基础。
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引用次数: 0
Prediction of homologous recombination deficiency from routine histology with attention-based multiple instance learning in nine different tumor types. 在九种不同肿瘤类型中,利用基于注意力的多实例学习,从常规组织学预测同源重组缺陷。
IF 4.4 1区 生物学 Q1 BIOLOGY Pub Date : 2024-10-08 DOI: 10.1186/s12915-024-02022-9
Chiara Maria Lavinia Loeffler, Omar S M El Nahhas, Hannah Sophie Muti, Zunamys I Carrero, Tobias Seibel, Marko van Treeck, Didem Cifci, Marco Gustav, Kevin Bretz, Nadine T Gaisa, Kjong-Van Lehmann, Alexandra Leary, Pier Selenica, Jorge S Reis-Filho, Nadina Ortiz-Bruechle, Jakob Nikolas Kather

Background: Homologous recombination deficiency (HRD) is recognized as a pan-cancer predictive biomarker that potentially indicates who could benefit from treatment with PARP inhibitors (PARPi). Despite its clinical significance, HRD testing is highly complex. Here, we investigated in a proof-of-concept study whether Deep Learning (DL) can predict HRD status solely based on routine hematoxylin & eosin (H&E) histology images across nine different cancer types.

Methods: We developed a deep learning pipeline with attention-weighted multiple instance learning (attMIL) to predict HRD status from histology images. As part of our approach, we calculated a genomic scar HRD score by combining loss of heterozygosity (LOH), telomeric allelic imbalance (TAI), and large-scale state transitions (LST) from whole genome sequencing (WGS) data of n = 5209 patients across two independent cohorts. The model's effectiveness was evaluated using the area under the receiver operating characteristic curve (AUROC), focusing on its accuracy in predicting genomic HRD against a clinically recognized cutoff value.

Results: Our study demonstrated the predictability of genomic HRD status in endometrial, pancreatic, and lung cancers reaching cross-validated AUROCs of 0.79, 0.58, and 0.66, respectively. These predictions generalized well to an external cohort, with AUROCs of 0.93, 0.81, and 0.73. Moreover, a breast cancer-trained image-based HRD classifier yielded an AUROC of 0.78 in the internal validation cohort and was able to predict HRD in endometrial, prostate, and pancreatic cancer with AUROCs of 0.87, 0.84, and 0.67, indicating that a shared HRD-like phenotype occurs across these tumor entities.

Conclusions: This study establishes that HRD can be directly predicted from H&E slides using attMIL, demonstrating its applicability across nine different tumor types.

背景:同源重组缺陷(HRD同源重组缺陷(HRD)被认为是一种泛癌症预测性生物标志物,有可能表明哪些人可以从 PARP 抑制剂(PARPi)的治疗中获益。尽管具有重要的临床意义,但 HRD 检测却非常复杂。在此,我们在一项概念验证研究中调查了深度学习(DL)能否仅根据常规苏木精和伊红(H&E)组织学图像预测九种不同癌症类型的 HRD 状态:我们利用注意力加权多实例学习(attMIL)开发了一个深度学习管道,用于从组织学图像预测HRD状态。作为方法的一部分,我们结合两个独立队列中5209名患者的全基因组测序(WGS)数据中的杂合性缺失(LOH)、端粒等位基因不平衡(TAI)和大规模状态转换(LST),计算出了基因组疤痕HRD评分。使用接收者操作特征曲线下面积(AUROC)对模型的有效性进行了评估,重点评估了该模型对照临床公认的临界值预测基因组HRD的准确性:我们的研究证明了基因组 HRD 状态在子宫内膜癌、胰腺癌和肺癌中的可预测性,经交叉验证的 AUROC 分别为 0.79、0.58 和 0.66。这些预测结果很好地推广到外部队列中,AUROC 分别为 0.93、0.81 和 0.73。此外,基于图像的乳腺癌HRD分类器在内部验证队列中的AUROC为0.78,并能预测子宫内膜癌、前列腺癌和胰腺癌的HRD,AUROC分别为0.87、0.84和0.67,这表明这些肿瘤实体存在类似HRD的共同表型:本研究证实,使用 attMIL 可以直接从 H&E 切片预测 HRD,并证明其适用于九种不同类型的肿瘤。
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