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Revealing taxonomy, activity, and substrate assimilation in mixed bacterial communities by GroEL-proteotyping-based stable isotope probing 通过基于 GroEL 蛋白分型的稳定同位素探测揭示混合细菌群落的分类、活性和底物同化作用

IF 4.6 2区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

iScience

Pub Date : 2024-10-28 DOI: 10.1016/j.isci.2024.111249

Simon Klaes , Shobhit Madan , Darja Deobald , Myriel Cooper , Lorenz Adrian

Protein-based stable isotope probing (protein-SIP) can link microbial taxa to substrate assimilation. Traditionally, protein-SIP requires a sample-specific metagenome-derived database for samples with unknown composition. Here, we describe GroEL-prototyping-based stable isotope probing (GroEL-SIP), that uses GroEL as a taxonomic marker protein to identify bacterial taxa (GroEL-proteotyping) coupled to SIP directly linking identified taxa to substrate consumption. GroEL-SIP’s main advantages are that (1) it can be performed with a sample-independent database and (2) sample complexity can be reduced by enriching GroEL proteins, increasing sensitivity and reducing instrument time. We applied GroEL-SIP to pure cultures, synthetic bicultures, and a human gut model using ²H-, ¹⁸O-, and ¹³C-labeled substrates. While ²H and ¹⁸O allowed assessing general activity, ¹³C enabled differentiation of substrate source and utilized metabolic pathways. GroEL-SIP offers fast and straightforward protein-SIP analyses of highly abundant families in mixed bacterial communities, but further work is needed to improve sensitivity, resolution, and database coverage.

基于蛋白质的稳定同位素探测（protein-SIP）可以将微生物类群与底物同化联系起来。传统上，蛋白质-SIP 需要一个特定于样本的元基因组数据库，用于未知成分的样本。在这里，我们介绍了基于GroEL-prototyping的稳定同位素探针（GroEL-SIP），它使用GroEL作为分类标记蛋白来识别细菌类群（GroEL-proteotyping），并结合SIP直接将已识别的类群与底物消耗联系起来。GroEL-SIP 的主要优点是：(1) 可使用与样品无关的数据库；(2) 可通过富集 GroEL 蛋白降低样品的复杂性，提高灵敏度并缩短仪器时间。我们使用 2H、18O 和 13C 标记的底物将 GroEL-SIP 应用于纯培养物、合成双培养物和人体肠道模型。2H 和 18O 可以评估一般活性，而 13C 则可以区分底物来源并利用代谢途径。GroEL-SIP为混合细菌群落中的高丰度家族提供了快速、直接的蛋白质-SIP分析，但还需要进一步的工作来提高灵敏度、分辨率和数据库覆盖率。

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引用次数: 0

A transcriptome-based risk model in sepsis enables prognostic prediction and drug repositioning 基于转录组的败血症风险模型可进行预后预测和药物重新定位

IF 4.6 2区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

iScience

Pub Date : 2024-10-28 DOI: 10.1016/j.isci.2024.111277

Qiuyue Long , Hongli Ye , Shixu Song , Jiwei Li , Jing Wu , Jingsong Mao , Ran Li , Ke Li , Zhancheng Gao , Yali Zheng

Septic management presented a tremendous challenge due to heterogeneous host responses. We aimed to develop a risk model for early septic stratification based on transcriptomic signature. Here, we combined genes OLAH, LY96, HPGD, and ABLIM1 into a prognostic risk score model, which demonstrated exceptional performance in septic diagnosis (AUC = 0.99–1.00) and prognosis (AUC = 0.61–0.70), outperforming that of Mars and SRS endotypes. Also, the model unveiled immunosuppressive status in high-risk patients and a poor response to hydrocortisone in low-risk individuals. Single-cell transcriptome analysis further elucidated expression patterns and effects of the four genes across immune cell types, illustrating integrated host responses reflected by this model. Upon distinct transcriptional profiles of risk subgroups, we identified fenretinide and meloxicam as therapeutic agents, which significantly improved survival in septic mice models. Our study introduced a risk model that optimized risk stratification and drug repurposing of sepsis, thereby offering a comprehensive management approach.

由于宿主反应的异质性，脓毒症的治疗面临巨大挑战。我们的目标是开发一种基于转录组特征的早期脓毒症分层风险模型。该模型在脓毒症诊断（AUC = 0.99-1.00）和预后（AUC = 0.61-0.70）方面表现优异，优于 Mars 和 SRS 内型。此外，该模型还揭示了高危患者的免疫抑制状态和低危患者对氢化可的松的不良反应。单细胞转录组分析进一步阐明了四种基因在不同免疫细胞类型中的表达模式和影响，说明了该模型所反映的综合宿主反应。根据风险亚组不同的转录特征，我们确定了芬瑞替尼和美洛昔康作为治疗药物，这两种药物能显著提高脓毒症小鼠模型的存活率。我们的研究引入了一种风险模型，可优化脓毒症的风险分层和药物再利用，从而提供一种全面的管理方法。

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引用次数: 0

C5aR1-positive adipocytes mediate non-shivering thermogenesis in neonatal mice C5aR1 阳性脂肪细胞介导新生小鼠非颤抖性产热

IF 4.6 2区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

iScience

Pub Date : 2024-10-28 DOI: 10.1016/j.isci.2024.111261

Huan-Yu Wang (汪欢玉) , Xue-Min Peng (彭雪敏) , Min Yang (杨敏) , Ying Weng (翁莹) , Xi Yang (杨希) , Di Zhan (詹迪) , Qin Ning (宁琴) , Xiao-Ping Luo (罗小平) , Yong Chen (陈勇)

Brown adipose tissue (BAT) plays an important role in maintaining body temperature in newborn mammals; however, its mechanisms remain poorly understood. Here, we report the identification of a special population of brown adipose tissue-derived stromal cells (ASCs) in neonatal mice that highly express CD45 and can be differentiated into adipocytes with lower thermogenic ability. These CD45⁺ adipocytes also characteristically contained complement C5a receptor 1(C5aR1) on the cell membrane. C5ar1 deficiency in BAT resulted in an apparent immaturity of adipocytes and cold intolerance in neonatal mice. Mechanistically, loss of C5aR1 in these CD45⁺ brown adipocytes caused an increase in the secretion of plate factor four (PF4) from these cells, suppressing the maturity of neighboring brown adipocytes. Overall, our results indicated that the accumulation of C5aR1 positive brown adipocyte in neonatal BAT is essential for thermoregulation in newborn mice, which unveiled the regulatory mechanism of BAT-mediated thermogenesis in newborns.

棕色脂肪组织（BAT）在维持新生哺乳动物体温方面发挥着重要作用；然而，人们对其机制仍然知之甚少。在这里，我们报告了在新生小鼠体内发现的棕色脂肪组织衍生基质细胞（ASCs）的特殊群体，它们高度表达 CD45，并能分化成具有较低生热能力的脂肪细胞。这些CD45+脂肪细胞的细胞膜上还含有补体C5a受体1（C5aR1）。BAT 中缺乏 C5ar1 会导致脂肪细胞明显不成熟和新生小鼠不耐寒。从机理上讲，这些 CD45+ 棕色脂肪细胞中 C5aR1 的缺失会导致这些细胞分泌的血小板因子四（PF4）增加，从而抑制邻近棕色脂肪细胞的成熟。总之，我们的研究结果表明，新生BAT中C5aR1阳性棕色脂肪细胞的积累对新生小鼠的体温调节至关重要，这揭示了新生小鼠BAT介导的产热调节机制。

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引用次数: 0

Diversity of nitrogen-fixing bacteria in Suaeda salsa rhizosphere during reproduction in the Yellow River delta 黄河三角洲 Suaeda salsa 根瘤菌繁殖过程中固氮菌的多样性

IF 4.6 2区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

iScience

Pub Date : 2024-10-28 DOI: 10.1016/j.isci.2024.111267

Deliang Xu , Qikang Wang , Meng Gao , Yating Li , Youjun Wang , Yuxin Jiang , Xiaohong Guo , Nan Wu

Salinization in the Yellow River delta poses a challenge for agriculture, but nitrogen-fixing bacteria can improve soil nitrogen content and enhance plant growth under salt stress. This study focuses on the salt-tolerant plant Suaeda salsa, analyzing its plant traits and the diversity of nitrogen-fixing bacteria in its rhizosphere using the nifH gene. Results show a gradual decline in plant height, fresh weight, and microbial diversity from inland to coastal areas. The rhizosphere bacteria, mainly from the Proteobacteria and Cyanobacteria phyla, are influenced by environmental factors such as alkali hydrolyzed nitrogen (AN), soil organic matter (SOM), electrical conductivity (EC), and pH. The rhizosphere serves as a microbial resource with potential agricultural applications for saline soils.

黄河三角洲的盐碱化给农业带来了挑战，但固氮菌可以提高土壤中的氮含量，促进植物在盐胁迫下的生长。本研究以耐盐植物 Suaeda salsa 为研究对象，利用 nifH 基因分析其植物性状及其根瘤中固氮菌的多样性。结果表明，从内陆到沿海地区，植物高度、鲜重和微生物多样性逐渐下降。根瘤菌主要来自变形菌门和蓝细菌门，受碱水解氮（AN）、土壤有机质（SOM）、电导率（EC）和 pH 值等环境因素的影响。根瘤菌圈是一种微生物资源，在盐碱地上具有潜在的农业应用价值。

引用次数: 0

Mathematical multi-compartment modeling of chronic lymphocytic leukemia cell kinetics under ibrutinib 伊布替尼作用下慢性淋巴细胞白血病细胞动力学的多室数学建模

IF 4.6 2区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

iScience

Pub Date : 2024-10-28 DOI: 10.1016/j.isci.2024.111242

Melanie Schulz , Sanne Bleser , Manouk Groels , Dragan Bošnački , Jan A. Burger , Nicholas Chiorazzi , Carsten Marr

The Bruton tyrosine kinase inhibitor ibrutinib is an effective treatment for patients with chronic lymphocytic leukemia (CLL). While it rapidly reduces lymph node and spleen size, it initially increases the number of lymphocytes in the blood due to cell redistribution. A previously published mathematical model described and quantified those cell kinetics. Here, we propose an alternative mechanistic model that outperforms the previous model in 26 of 29 patients. Our model introduces constant subcompartments for healthy lymphocytes and benign tissue and treats spleen and lymph nodes as separate compartments. This three-compartment model (comprising blood, spleen, and lymph nodes) performed significantly better in patients without a mutation in the IGHV gene, indicating a diverse response to ibrutinib for cells residing in lymph nodes and spleen. Additionally, high ZAP-70 expression was linked to less cell death in the spleen. Overall, our study enhances understanding of CLL genetics and patient response to ibrutinib and provides a framework applicable to the study of similar drugs.

布鲁顿酪氨酸激酶抑制剂伊布替尼是治疗慢性淋巴细胞白血病（CLL）患者的有效药物。它在迅速缩小淋巴结和脾脏体积的同时，由于细胞的重新分布，最初会增加血液中的淋巴细胞数量。以前发表的一个数学模型描述并量化了这些细胞动力学。在此，我们提出了另一种机理模型，该模型在 29 例患者中的 26 例效果优于之前的模型。我们的模型为健康淋巴细胞和良性组织引入了恒定的亚室，并将脾脏和淋巴结视为独立的室。这种三室模型（包括血液、脾脏和淋巴结）在没有 IGHV 基因突变的患者中表现明显更好，表明淋巴结和脾脏中的细胞对依鲁替尼的反应是多样的。此外，ZAP-70的高表达与脾脏中较少的细胞死亡有关。总之，我们的研究加深了人们对CLL遗传学和患者对伊布替尼反应的了解，并提供了一个适用于类似药物研究的框架。

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引用次数: 0

Adjuvant treatment after neoadjuvant immunotherapy in patients with non-small cell lung cancer 非小细胞肺癌患者接受新辅助免疫疗法后的辅助治疗

IF 4.6 2区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

iScience

Pub Date : 2024-10-28 DOI: 10.1016/j.isci.2024.111281

Junfeng Zhao , Ying Li , Ruyue Li , Xiujing Yao , Xue Dong , Lin Su , Yintao Li

This study explored the feasibility of adjuvant immunotherapy after NICT and surgery. A retrospective study was conducted on NSCLC patients who underwent NICT and surgery. Two patient groups were defined based on their adjuvant therapy after NICT and surgery: the Chemo group (chemotherapy alone) and the Immuno+Chemo group (chemotherapy combined with immunotherapy). Disease-free survival (DFS) and overall survival (OS) were also analyzed. In total, 209 patients were enrolled. The median DFS for the Immuno+Chemo group and the Chemo group was not reached vs. 26 months (hazard ratio [HR]: 0.498, 95% confidence interval [CI]: 0.315–0.787, p = 0.002). A significant difference in OS was also observed; however, the median OS was not reached in either group (HR: 0.526, 95% CI: 0.287–0.965, p = 0.034). Postoperative adjuvant chemotherapy combined with immunotherapy was significantly more effective than adjuvant chemotherapy alone in patients with NSCLC treated with NICT and surgery.

这项研究探讨了在NICT和手术后进行辅助免疫疗法的可行性。这项回顾性研究针对接受了 NICT 和手术的 NSCLC 患者。根据NICT和手术后的辅助治疗情况将患者分为两组：化疗组（单纯化疗）和免疫+化疗组（化疗联合免疫治疗）。此外，还对无病生存期（DFS）和总生存期（OS）进行了分析。共有 209 名患者入组。免疫+化疗组和化疗组的中位无病生存期分别为 26 个月（危险比 [HR]：0.498，95% 置信区间 [CI]：0.315-0.787, p = 0.002).此外，还观察到 OS 方面的明显差异；不过，两组患者均未达到中位 OS（HR：0.526，95% CI：0.287-0.965，P = 0.034）。在接受NICT和手术治疗的NSCLC患者中，术后辅助化疗联合免疫疗法的疗效明显优于单纯辅助化疗。

引用次数: 0

The strand exchange domain of tumor suppressor PALB2 is intrinsically disordered and promotes oligomerization-dependent DNA compaction 肿瘤抑制因子 PALB2 的链交换结构域具有内在无序性，可促进寡聚化依赖性 DNA 压实

IF 4.6 2区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

iScience

Pub Date : 2024-10-28 DOI: 10.1016/j.isci.2024.111259

Yevhenii Kyriukha , Maxwell B. Watkins , Jennifer M. Redington , Nithya Chintalapati , Abhishek Ganti , Reza Dastvan , Vladimir N. Uversky , Jesse B. Hopkins , Nicola Pozzi , Sergey Korolev

The partner and localizer of BRCA2 (PALB2) is a scaffold protein linking BRCA1 with BRCA2 and RAD51 during homologous recombination (HR). PALB2 interaction with DNA strongly enhances HR in cells, while the PALB2 DNA-binding domain (PALB2-DBD) supports DNA strand exchange in vitro. We determined that PALB2-DBD is intrinsically disordered beyond a single N-terminal α-helix. Coiled-coil mediated dimerization is stabilized by interaction between intrinsically disordered regions (IDRs) leading to a 2-fold structural compaction. Single-stranded (ss)DNA binding promotes additional structural compaction and protein tetramerization. Using confocal single-molecule FRET, we observed bimodal and oligomerization-dependent compaction of ssDNA bound to PALB2-DBD, suggesting a novel strand exchange mechanism. Bioinformatics analysis and preliminary observations indicate that PALB2 forms protein-nucleic acids condensates. Intrinsically disordered DBDs are prevalent in the human proteome. PALB2-DBD and similar IDRs may use a chaperone-like mechanism to aid formation and resolution of DNA and RNA multichain intermediates during DNA replication, repair and recombination.

BRCA2 的伙伴和定位器（PALB2）是同源重组（HR）过程中连接 BRCA1 与 BRCA2 和 RAD51 的支架蛋白。PALB2 与 DNA 的相互作用可强烈增强细胞中的 HR，而 PALB2 DNA 结合域（PALB2-DBD）则支持体外 DNA 链交换。我们确定，PALB2-DBD 除了单个 N 端 α 螺旋外，在本质上是无序的。盘绕线圈介导的二聚化通过内在无序区（IDRs）之间的相互作用而稳定，从而导致结构压缩 2 倍。单链（ss）DNA 的结合促进了额外的结构压实和蛋白质四聚化。利用共聚焦单分子 FRET，我们观察到了与 PALB2-DBD 结合的 ssDNA 的双峰和寡聚依赖性压实，这表明了一种新的链交换机制。生物信息学分析和初步观察表明，PALB2 形成了蛋白质-核酸凝聚体。本质上无序的 DBD 在人类蛋白质组中非常普遍。PALB2-DBD和类似的IDRs可能利用类似于伴侣的机制，在DNA复制、修复和重组过程中帮助DNA和RNA多链中间体的形成和解析。

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引用次数: 0

Hard shell, soft blue-green core: Ecology, processes, and modern applications of calcification in terrestrial cyanobacteria 坚硬的外壳，柔软的蓝绿内核：陆生蓝藻钙化的生态学、过程和现代应用

IF 4.6 2区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

iScience

Pub Date : 2024-10-28 DOI: 10.1016/j.isci.2024.111280

Patrick Jung , Laura Briegel-Williams , Stefan Dultz , Carina Neff , Gunnar Heibrock , Curtis Monger , Nicole Pietrasiak , Lena Keller , Julia Hale , Jan Friedek , Timo Schmidt , Georg Guggenberger , Michael Lakatos

Cyanobacteria are the oldest photoautotrophic lineage that release oxygen during photosynthesis, an ability that possibly evolved as far as 3.5 billion years ago and changed the Earth’s environment—both in water and on land. Linked to the mechanism of carbon accumulation by cyanobacteria during photosynthesis are their calcifying properties, a process of biologically mediated mineralization of CO₂ by precipitation with calcium to CaCO₃. In recent decades, scientific research has mainly focused on calcifying cyanobacteria from aquatic habitats, while their terrestrial relatives have been neglected. This review not only presents the ecology of terrestrial calcifying cyanobacteria in caves and biocrusts but also discusses recent biotechnological applications, such as the production of living building materials through microbial-induced carbonate precipitation for structural engineering, which has the potential to open a new and efficient pathway for mitigating climate change, e.g., as carbon capture and storage technology.

蓝藻是最古老的光自养菌系，能在光合作用中释放氧气，这种能力可能早在 35 亿年前就已经进化出来，并改变了地球的环境--无论是在水中还是在陆地上。蓝藻在光合作用过程中积累碳的机制与蓝藻的钙化特性有关，钙化是通过生物媒介将二氧化碳与钙沉淀成 CaCO3 的矿化过程。近几十年来，科学研究主要集中在水生环境中的钙化蓝藻，而陆生环境中的钙化蓝藻却被忽视。这篇综述不仅介绍了洞穴和生物簇中陆生钙化蓝藻的生态学，还讨论了最近的生物技术应用，如通过微生物诱导碳酸盐沉淀生产活的建筑材料，用于结构工程，这有可能为减缓气候变化开辟一条新的有效途径，如作为碳捕获和储存技术。

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引用次数: 0

Circuit mechanism underlying fragmented sleep and memory deficits in 16p11.2 deletion mouse model of autism 16p11.2缺失小鼠自闭症模型中片段睡眠和记忆缺陷的回路机制

IF 4.6 2区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

iScience

Pub Date : 2024-10-28 DOI: 10.1016/j.isci.2024.111285

Ashley Choi , Bowon Kim , Eleanor Labriola , Alyssa Wiest , Yingqi Wang , Jennifer Smith , Hyunsoo Shin , Xi Jin , Isabella An , Jiso Hong , Hanna Antila , Steven Thomas , Janardhan P. Bhattarai , Kevin Beier , Minghong Ma , Franz Weber , Shinjae Chung

Sleep disturbances are prevalent in children with autism spectrum disorder (ASD). Strikingly, sleep problems are positively correlated with the severity of ASD symptoms, such as memory impairment. However, the neural mechanisms underlying sleep disturbances and cognitive deficits in ASD are largely unexplored. Here, we show that non-rapid eye movement sleep (NREMs) is fragmented in the 16p11.2 deletion mouse model of ASD. The degree of sleep fragmentation is reflected in an increased number of calcium transients in the activity of locus coeruleus noradrenergic (LC-NE) neurons during NREMs. In contrast, optogenetic inhibition of LC-NE neurons and pharmacological blockade of noradrenergic transmission using clonidine consolidate sleep. Furthermore, inhibiting LC-NE neurons restores memory. Finally, rabies-mediated screening of presynaptic neurons reveals altered connectivity of LC-NE neurons with sleep- and memory-regulatory regions in 16p11.2 deletion mice. Our findings identify a crucial role of the LC-NE system in regulating sleep stability and memory in ASD.

自闭症谱系障碍（ASD）儿童普遍存在睡眠障碍。令人震惊的是，睡眠问题与自闭症症状（如记忆障碍）的严重程度呈正相关。然而，自闭症谱系障碍儿童睡眠障碍和认知缺陷的神经机制在很大程度上尚未得到研究。在这里，我们发现在16p11.2缺失的ASD小鼠模型中，非快速眼动睡眠（NREMs）是片段的。睡眠片段化的程度反映在非快速眼动睡眠（NREMs）期间，脑室小脑去甲肾上腺素能（LC-NE）神经元活动中的钙瞬态数量增加。相反，光遗传抑制 LC-NE 神经元和使用氯尼丁药物阻断去甲肾上腺素能传导可巩固睡眠。此外，抑制 LC-NE 神经元还能恢复记忆。最后，狂犬病介导的突触前神经元筛查发现，16p11.2 缺失小鼠的 LC-NE 神经元与睡眠和记忆调节区域的连接发生了改变。我们的研究结果确定了 LC-NE 系统在 ASD 中调节睡眠稳定性和记忆的关键作用。

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引用次数: 0

Erratum: Safety and improved efficacy signals following gene therapy in childhood blindness caused by GUCY2D mutations. 勘误：GUCY2D 基因突变导致儿童失明的基因治疗安全性和疗效改善信号。

IF 4.6 2区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

iScience

Pub Date : 2024-10-28 eCollection Date: 2024-11-15 DOI: 10.1016/j.isci.2024.111048

Samuel G Jacobson, Artur V Cideciyan, Allen C Ho, Igor V Peshenko, Alexandra V Garafalo, Alejandro J Roman, Alexander Sumaroka, Vivian Wu, Arun K Krishnan, Rebecca Sheplock, Sanford L Boye, Alexander M Dizhoor, Shannon E Boye

[This corrects the article DOI: 10.1016/j.isci.2021.102409.].

[此处更正文章 DOI：10.1016/j.isci.2021.102409.]。

引用次数: 0

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