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HIV-1-induced translocation of CPSF6 to biomolecular condensates. HIV-1 诱导的 CPSF6 向生物分子凝聚体的转运。
IF 14 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-01 Epub Date: 2024-01-23 DOI: 10.1016/j.tim.2024.01.001
Katarzyna Bialas, Felipe Diaz-Griffero

Cleavage and polyadenylation specificity factor subunit 6 (CPSF6, also known as CFIm68) is a 68 kDa component of the mammalian cleavage factor I (CFIm) complex that modulates mRNA alternative polyadenylation (APA) and determines 3' untranslated region (UTR) length, an important gene expression control mechanism. CPSF6 directly interacts with the HIV-1 core during infection, suggesting involvement in HIV-1 replication. Here, we review the contributions of CPSF6 to every stage of the HIV-1 replication cycle. Recently, several groups described the ability of HIV-1 infection to induce CPSF6 translocation to nuclear speckles, which are biomolecular condensates. We discuss the implications for CPSF6 localization in condensates and the potential role of condensate-localized CPSF6 in the ability of HIV-1 to control the protein expression pattern of the cell.

裂解和多腺苷酸化特异性因子亚基 6(CPSF6,又称 CFIm68)是哺乳动物裂解因子 I(CFIm)复合物的一个 68 kDa 组份,可调节 mRNA 替代多腺苷酸化(APA)并决定 3' 非翻译区(UTR)长度,这是一种重要的基因表达控制机制。CPSF6 在感染过程中与 HIV-1 核心直接相互作用,表明它参与了 HIV-1 的复制。在此,我们回顾了 CPSF6 对 HIV-1 复制周期各个阶段的贡献。最近,几个研究小组描述了 HIV-1 感染诱导 CPSF6 转位至核斑点(一种生物分子凝聚物)的能力。我们讨论了 CPSF6 在凝聚体中定位的意义,以及凝聚体定位的 CPSF6 在 HIV-1 控制细胞蛋白质表达模式的能力中的潜在作用。
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引用次数: 0
The microbiota's role in flavivirus control: Rosenbergiella_YN46. 微生物群在黄病毒控制中的作用:Rosenbergiella_YN46。
IF 14 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-01 Epub Date: 2024-06-08 DOI: 10.1016/j.tim.2024.05.009
Biao Hu, Jianping Chen, Zongtao Sun

The transmission of flaviviruses, such as dengue virus (DENV) and Zika virus (ZIKV), poses a significant threat to global public health. Zhang et al. recently showed that Rosenbergiella sp. YN46 (Rosenbergiella_YN46), a bacterium from the mosquito gut, inhibits flavivirus transmission and thus offers a potential biocontrol strategy with broad public health implications.

登革病毒(DENV)和寨卡病毒(ZIKV)等黄病毒的传播对全球公共卫生构成了重大威胁。Zhang 等人最近研究发现,蚊子肠道中的一种细菌 Rosenbergiella sp.
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引用次数: 0
Deciphering Fc-effector functions against SARS-CoV-2. 解密 Fc-效应器对抗 SARS-CoV-2 的功能
IF 14 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-01 Epub Date: 2024-02-15 DOI: 10.1016/j.tim.2024.01.005
Guillaume Beaudoin-Bussières, Andrés Finzi

Major efforts were deployed to study the antibody response against SARS-CoV-2. Antibodies neutralizing SARS-CoV-2 have been extensively studied in the context of infections, vaccinations, and breakthrough infections. Antibodies, however, are pleiotropic proteins that have many functions in addition to neutralization. These include Fc-effector functions such as antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). Although important to combat viral infections, these Fc-effector functions were less studied in the context of SARS-CoV-2 compared with binding and neutralization. This is partly due to the difficulty in developing reliable assays to measure Fc-effector functions compared to antibody binding and neutralization. Multiple assays have now been developed and can be used to measure different Fc-effector functions. Here, we review these assays and what is known regarding anti-SARS-CoV-2 Fc-effector functions. Overall, this review summarizes and updates our current state of knowledge regarding anti-SARS-CoV-2 Fc-effector functions.

研究针对 SARS-CoV-2 的抗体反应是一项重要工作。在感染、疫苗接种和突破性感染方面,对中和 SARS-CoV-2 的抗体进行了广泛的研究。然而,抗体是一种多效蛋白,除了中和作用外,还具有多种功能。这些功能包括 Fc 效应器功能,如抗体依赖性细胞毒性(ADCC)和抗体依赖性细胞吞噬作用(ADCP)。虽然这些 Fc 效应功能对抗病毒感染很重要,但与结合和中和相比,对 SARS-CoV-2 的研究较少。部分原因是,与抗体结合和中和相比,很难开发出可靠的检测方法来测量 Fc-效应器功能。目前已开发出多种检测方法,可用于测量不同的 Fc-效应器功能。在此,我们回顾了这些检测方法以及目前已知的抗 SARS-CoV-2 Fc-效应器功能。总之,本综述总结并更新了我们目前对抗 SARS-CoV-2 Fc-效应器功能的了解。
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引用次数: 0
Broadening the targetable space: engineering and discovery of PAM-flexible Cas proteins. 拓宽靶向空间:PAM 灵活 Cas 蛋白的工程设计与发现。
IF 14 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-01 Epub Date: 2024-05-29 DOI: 10.1016/j.tim.2024.05.004
Zhenkun Cai, Weiyu Xie, Zehua Bao

The application of CRISPR-Cas systems has been hindered by their requirement for long protospacer-adjacent motifs (PAMs). Recent engineering and discovery of PAM-flexible Cas proteins have substantially broadened the targetable DNA sequence space, thereby facilitating genome editing and improving derivative technologies such as gene regulation, seamless cloning, and large-scale genetic screens.

CRISPR-Cas系统的应用一直受制于对长原位相邻基序(PAM)的要求。最近,PAM 灵活 Cas 蛋白的工程设计和发现大大拓宽了可靶向的 DNA 序列空间,从而促进了基因组编辑,并改善了基因调控、无缝克隆和大规模基因筛选等衍生技术。
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引用次数: 0
Forecasting antimicrobial resistance evolution. 预测抗菌药耐药性的演变。
IF 14 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-01 Epub Date: 2024-01-18 DOI: 10.1016/j.tim.2023.12.009
Jens Rolff, Sebastian Bonhoeffer, Charlotte Kloft, Rasmus Leistner, Roland Regoes, Michael E Hochberg

Antimicrobial resistance (AMR) is a major global health issue. Current measures for tackling it comprise mainly the prudent use of drugs, the development of new drugs, and rapid diagnostics. Relatively little attention has been given to forecasting the evolution of resistance. Here, we argue that forecasting has the potential to be a great asset in our arsenal of measures to tackle AMR. We argue that, if successfully implemented, forecasting resistance will help to resolve the antibiotic crisis in three ways: it will (i) guide a more sustainable use (and therefore lifespan) of antibiotics and incentivize investment in drug development, (ii) reduce the spread of AMR genes and pathogenic microbes in the environment and between patients, and (iii) allow more efficient treatment of persistent infections, reducing the continued evolution of resistance. We identify two important challenges that need to be addressed for the successful establishment of forecasting: (i) the development of bespoke technology that allows stakeholders to empirically assess the risks of resistance evolving during the process of drug development and therapeutic/preventive use, and (ii) the transformative shift in mindset from the current praxis of mostly addressing the problem of antibiotic resistance a posteriori to a concept of a priori estimating, and acting on, the risks of resistance.

抗菌药耐药性(AMR)是一个重大的全球健康问题。目前的应对措施主要包括谨慎用药、开发新药和快速诊断。人们对耐药性演变的预测关注相对较少。在此,我们认为,预测有可能成为我们应对 AMR 的措施库中的一项重要资产。我们认为,如果能够成功实施,抗药性预测将有助于从三个方面解决抗生素危机:(i) 指导更可持续地使用抗生素(从而延长抗生素的寿命),激励对药物开发的投资;(ii) 减少 AMR 基因和病原微生物在环境中和病人之间的传播;(iii) 更有效地治疗顽固性感染,减少抗药性的持续演变。我们发现,要成功建立预测机制,需要应对两个重要挑战:(i) 开发定制技术,使利益相关者能够在药物开发和治疗/预防使用过程中对耐药性演变的风险进行经验评估;(ii) 转变观念,从目前主要在事后解决抗生素耐药性问题的做法转变为事先估计耐药性风险并采取相应行动的理念。
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引用次数: 0
Breaking bad nucleotides: understanding the regulatory mechanisms of bacterial small alarmone hydrolases. 打破不良核苷酸:了解细菌小报警酮水解酶的调控机制。
IF 14 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-01 Epub Date: 2024-01-22 DOI: 10.1016/j.tim.2023.12.011
Adriana Chrenková, Francesco Bisiak, Ditlev E Brodersen

Guanosine tetra- and pentaphosphate nucleotides, (p)ppGpp, function as central secondary messengers and alarmones in bacterial cell biology, signalling a range of stress conditions, including nutrient starvation and exposure to cell-wall-targeting antibiotics, and are critical for survival. While activation of the stringent response and alarmone synthesis on starved ribosomes by members of the RSH (Rel) class of proteins is well understood, much less is known about how single-domain small alarmone synthetases (SASs) and their corresponding alarmone hydrolases, the small alarmone hydrolases (SAHs), are regulated and contribute to (p)ppGpp homeostasis. The substrate spectrum of these enzymes has recently been expanded to include hyperphosphorylated adenosine nucleotides, suggesting that they take part in a highly complex and interconnected signalling network. In this review, we provide an overview of our understanding of the SAHs and discuss their structure, function, regulation, and phylogeny.

四磷酸和五磷酸鸟苷核苷酸((p)ppGpp)是细菌细胞生物学中的核心次级信使和警报素,可发出一系列应激信号,包括营养饥饿和暴露于细胞壁靶向抗生素,对生存至关重要。虽然人们对 RSH(Rel)类蛋白激活严格反应和饥饿核糖体上的报警酮合成已经有了很好的了解,但对单链小报警酮合成酶(SAS)及其相应的报警酮水解酶--小报警酮水解酶(SAH)--如何调节和促进(pp)ppGpp 稳态却知之甚少。这些酶的底物谱最近已扩大到包括过磷酸化腺苷核苷酸,这表明它们参与了一个高度复杂和相互关联的信号网络。在这篇综述中,我们概述了我们对 SAHs 的了解,并讨论了它们的结构、功能、调控和系统发育。
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引用次数: 0
Immunological roads diverged: mapping tuberculosis outcomes in mice. 免疫学道路上的分歧:绘制小鼠结核病结果图。
IF 14 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-20 DOI: 10.1016/j.tim.2024.06.007
Rachel K Meade, Clare M Smith

The journey from phenotypic observation to causal genetic mechanism is a long and challenging road. For pathogens like Mycobacterium tuberculosis (Mtb), which causes tuberculosis (TB), host-pathogen coevolution has spanned millennia, costing millions of human lives. Mammalian models can systematically recapitulate host genetic variation, producing a spectrum of disease outcomes. Leveraging genome sequences and deep phenotyping data from infected mouse genetic reference populations (GRPs), quantitative trait locus (QTL) mapping approaches have successfully identified host genomic regions associated with TB phenotypes. Here, we review the ongoing optimization of QTL mapping study design alongside advances in mouse GRPs. These next-generation resources and approaches have enabled identification of novel host-pathogen interactions governing one of the most prevalent infectious diseases in the world today.

从表型观察到因果遗传机制是一条漫长而充满挑战的道路。对于结核分枝杆菌(Mtb)等导致肺结核(TB)的病原体来说,宿主与病原体的共同进化跨越了数千年,夺走了数百万人的生命。哺乳动物模型可以系统地再现宿主基因变异,产生一系列疾病结果。利用基因组序列和来自受感染小鼠遗传参考群体(GRPs)的深度表型数据,定量性状位点(QTL)绘图方法已成功鉴定出与结核病表型相关的宿主基因组区域。在此,我们回顾了 QTL 图谱研究设计的不断优化以及小鼠 GRPs 的进步。这些下一代资源和方法使我们能够鉴定新的宿主-病原体相互作用,从而控制当今世界上最流行的传染病之一。
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引用次数: 0
Cell-free DNA: a promising biomarker in infectious diseases. 无细胞 DNA:传染性疾病中一种前景广阔的生物标记物。
IF 14 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-11 DOI: 10.1016/j.tim.2024.06.005
Yuxuan Hu, Yanping Zhao, Yan Zhang, Weijun Chen, Haiqiang Zhang, Xin Jin

Infectious diseases pose serious threats to public health worldwide. Conventional diagnostic methods for infectious diseases often exhibit low sensitivity, invasiveness, and long turnaround times. User-friendly point-of-care tests are urgently needed for early diagnosis, treatment monitoring, and prognostic prediction of infectious diseases. Cell-free DNA (cfDNA), a promising non-invasive biomarker widely used in oncology and pregnancy, has shown great potential in clinical applications for diagnosing infectious diseases. Here, we discuss the most recent cfDNA research on infectious diseases from both the pathogen and host perspectives. We also discuss the technical challenges in this field and propose solutions to overcome them. Additionally, we provide an outlook on the potential of cfDNA as a diagnostic, treatment, and prognostic marker for infectious diseases.

传染病对全球公共卫生构成严重威胁。传统的传染病诊断方法往往灵敏度低、侵入性大、周转时间长。传染病的早期诊断、治疗监测和预后预测迫切需要方便用户的床旁检测。无细胞 DNA(cfDNA)是一种前景广阔的非侵入性生物标记物,被广泛应用于肿瘤学和妊娠学领域,在传染病诊断的临床应用中也显示出巨大的潜力。在此,我们将从病原体和宿主的角度讨论有关传染性疾病的最新 cfDNA 研究。我们还讨论了这一领域的技术挑战,并提出了克服这些挑战的解决方案。此外,我们还对 cfDNA 作为传染病诊断、治疗和预后标志物的潜力进行了展望。
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引用次数: 0
Influence of antimicrobial peptides on the bacterial membrane curvature and vice versa. 抗菌肽对细菌膜曲率的影响,反之亦然。
IF 14 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-01 Epub Date: 2024-05-21 DOI: 10.1016/j.tim.2024.04.012
Marlon H Cardoso, Cesar de la Fuente-Nunez, Nuno C Santos, Michael A Zasloff, Octávio L Franco

Many factors contribute to bacterial membrane stabilization, including steric effects between lipids, membrane spontaneous curvature, and the difference in the number of neighboring molecules. This forum provides an overview of the physicochemical properties associated with membrane curvature and how this parameter can be tuned to design more effective antimicrobial peptides.

导致细菌膜稳定的因素有很多,包括脂质之间的立体效应、膜自发曲率以及相邻分子数量的差异。本论坛概述了与膜曲率相关的物理化学特性,以及如何调整这一参数以设计出更有效的抗菌肽。
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引用次数: 0
Viruses shuttle between fungi and plants. 病毒在真菌和植物之间穿梭。
IF 14 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-01 Epub Date: 2024-05-07 DOI: 10.1016/j.tim.2024.04.013
Jichun Jia, Daohong Jiang, Jiatao Xie

The intimate relationships between plants and fungi provide an opportunity for the shuttling of viruses. Dai et al. recently discovered that a virus undergoes cross-kingdom transmission, and naturally spreads to both plant and fungal populations. This finding expands our understanding of viral host range, evolution, transmission, and disease management.

植物与真菌之间的密切关系为病毒的穿梭提供了机会。Dai 等人最近发现,一种病毒可以进行跨领域传播,自然扩散到植物和真菌种群中。这一发现拓展了我们对病毒宿主范围、进化、传播和疾病管理的认识。
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引用次数: 0
期刊
Trends in Microbiology
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