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Can we manipulate the ovary's own metabolism to protect it from chemotherapy-induced damage? 我们能否操纵卵巢自身的新陈代谢,使其免受化疗引起的损害?
IF 9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-01 Epub Date: 2024-09-03 DOI: 10.1038/s44321-024-00124-z
Adomas Liugaila, Agnes Stefansdottir, Norah Spears
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引用次数: 0
Human breast tissue engineering in health and disease. 健康与疾病中的人体乳腺组织工程。
IF 9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-01 Epub Date: 2024-08-23 DOI: 10.1038/s44321-024-00112-3
Maj-Britt Buchholz, Demi I Scheerman, Riccardo Levato, Ellen J Wehrens, Anne C Rios

The human mammary gland represents a highly organized and dynamic tissue, uniquely characterized by postnatal developmental cycles. During pregnancy and lactation, it undergoes extensive hormone-stimulated architectural remodeling, culminating in the formation of specialized structures for milk production to nourish offspring. Moreover, it carries significant health implications, due to the high prevalence of breast cancer. Therefore, gaining insight into the unique biology of the mammary gland can have implications for managing breast cancer and promoting the well-being of both women and infants. Tissue engineering techniques hold promise to narrow the translational gap between existing breast models and clinical outcomes. Here, we provide an overview of the current landscape of breast tissue engineering, outline key requirements, and the challenges to overcome for achieving more predictive human breast models. We propose methods to validate breast function and highlight preclinical applications for improved understanding and targeting of breast cancer. Beyond mammary gland physiology, representative human breast models can offer new insight into stem cell biology and developmental processes that could extend to other organs and clinical contexts.

人类乳腺是一种高度组织化的动态组织,具有产后发育周期的独特特征。在怀孕和哺乳期间,乳腺在激素的刺激下经历了广泛的结构重塑,最终形成专门的乳汁分泌结构,以滋养后代。此外,由于乳腺癌的高发病率,它对健康也有重大影响。因此,深入了解乳腺的独特生物学特性对控制乳腺癌、促进妇女和婴儿的健康都有意义。组织工程技术有望缩小现有乳腺模型与临床结果之间的转化差距。在此,我们概述了乳腺组织工程的现状,概述了实现更具预测性的人类乳腺模型的关键要求和需要克服的挑战。我们提出了验证乳房功能的方法,并重点介绍了临床前应用,以提高对乳腺癌的理解和靶向治疗。除乳腺生理学外,具有代表性的人类乳房模型还能为干细胞生物学和发育过程提供新的见解,并可扩展到其他器官和临床环境。
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引用次数: 0
Next generation of "magic bullets", solutions from the microbial pangenome. 下一代 "灵丹妙药",来自微生物泛基因组的解决方案。
IF 9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-01 Epub Date: 2024-09-06 DOI: 10.1038/s44321-024-00133-y
Vega Masignani, Rino Rappuoli, Mariagrazia Pizza
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引用次数: 0
Infection length and host environment influence on Plasmodium falciparum dry season reservoir. 感染时间和宿主环境对恶性疟原虫旱季储库的影响
IF 9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-01 Epub Date: 2024-09-16 DOI: 10.1038/s44321-024-00127-w
Carolina M Andrade, Manuela Carrasquilla, Usama Dabbas, Jessica Briggs, Hannah van Dijk, Nikolay Sergeev, Awa Sissoko, Moussa Niangaly, Christina Ntalla, Emily LaVerriere, Jeff Skinner, Klara Golob, Jeremy Richter, Hamidou Cisse, Shanping Li, Jason A Hendry, Muhammad Asghar, Didier Doumtabe, Anna Farnert, Thomas Ruppert, Daniel E Neafsey, Kassoum Kayentao, Safiatou Doumbo, Aissata Ongoiba, Peter D Crompton, Boubacar Traore, Bryan Greenhouse, Silvia Portugal

Persistence of malaria parasites in asymptomatic hosts is crucial in areas of seasonally-interrupted transmission, where P. falciparum bridges wet seasons months apart. During the dry season, infected erythrocytes exhibit extended circulation with reduced cytoadherence, increasing the risk of splenic clearance of infected cells and hindering parasitaemia increase. However, what determines parasite persistence for long periods of time remains unknown. Here, we investigated whether seasonality affects plasma composition so that P. falciparum can detect and adjust to changing serological cues; or if alternatively, parasite infection length dictates clinical presentation and persistency. Data from Malian children exposed to alternating ~6-month wet and dry seasons show that plasma composition is unrelated to time of year in non-infected children, and that carrying P. falciparum only minimally affects plasma constitution in asymptomatic hosts. Parasites persisting in the blood of asymptomatic children from the dry into the ensuing wet season rarely if ever appeared to cause malaria in their hosts as seasons changed. In vitro culture in the presence of plasma collected in the dry or the wet seasons did not affect parasite development, replication or host-cell remodelling. The absence of a parasite-encoded sensing mechanism was further supported by the observation of similar features in P. falciparum persisting asymptomatically in the dry season and parasites in age- and sex-matched asymptomatic children in the wet season. Conversely, we show that P. falciparum clones transmitted early in the wet season had lower chance of surviving until the end of the following dry season, contrasting with a higher likelihood of survival of clones transmitted towards the end of the wet season, allowing for the re-initiation of transmission. We propose that the decreased virulence observed in persisting parasites during the dry season is not due to the parasites sensing ability, nor is it linked to a decreased capacity for parasite replication but rather a consequence decreased cytoadhesion associated with infection length.

在恶性疟原虫传播季节性中断的地区,疟原虫在无症状宿主体内的持续存在至关重要。在旱季,受感染的红细胞循环时间延长,细胞粘附性降低,增加了脾脏清除受感染细胞的风险,阻碍了寄生虫血症的增加。然而,决定寄生虫长期存在的因素仍然未知。在此,我们研究了季节性是否会影响血浆成分,从而使恶性疟原虫能够检测到并适应不断变化的血清学线索;或者,寄生虫感染时间的长短是否决定了临床表现和持续性。来自马里儿童的数据显示,非感染儿童的血浆组成与一年中的时间无关,携带恶性疟原虫对无症状宿主的血浆组成影响很小。从旱季到雨季,寄生在无症状儿童血液中的寄生虫很少会随着季节的变化在宿主体内引起疟疾。在有旱季或雨季采集的血浆存在的情况下进行体外培养,不会影响寄生虫的发育、复制或宿主细胞重塑。在旱季无症状的恶性疟原虫和在雨季年龄和性别匹配的无症状儿童体内的寄生虫中观察到类似的特征,这进一步证实了不存在寄生虫编码的感应机制。相反,我们的研究表明,在雨季早期传播的恶性疟原虫克隆存活到下一个旱季结束的几率较低,而在雨季末期传播的克隆存活几率较高,这使得传播得以重新开始。我们认为,在旱季持续存在的寄生虫中观察到的毒力下降并不是因为寄生虫的感知能力下降,也与寄生虫复制能力下降无关,而是与感染时间长短相关的细胞粘附力下降的结果。
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引用次数: 0
Rational structure-guided design of a blood stage malaria vaccine immunogen presenting a single epitope from PfRH5. 以结构为导向合理设计血期疟疾疫苗免疫原,呈现 PfRH5 的单一表位。
IF 9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-01 Epub Date: 2024-09-02 DOI: 10.1038/s44321-024-00123-0
Thomas E Harrison, Nawsad Alam, Brendan Farrell, Doris Quinkert, Amelia M Lias, Lloyd D W King, Lea K Barfod, Simon J Draper, Ivan Campeotto, Matthew K Higgins

There is an urgent need for improved malaria vaccine immunogens. Invasion of erythrocytes by Plasmodium falciparum is essential for its life cycle, preceding symptoms of disease and parasite transmission. Antibodies which target PfRH5 are highly effective at preventing erythrocyte invasion and the most potent growth-inhibitory antibodies bind a single epitope. Here we use structure-guided approaches to design a small synthetic immunogen, RH5-34EM which recapitulates this epitope. Structural biology and biophysics demonstrate that RH5-34EM is correctly folded and binds neutralising monoclonal antibodies with nanomolar affinity. In immunised rats, RH5-34EM induces PfRH5-targeting antibodies that inhibit parasite growth. While PfRH5-specific antibodies were induced at a lower concentration by RH5-34EM than by PfRH5, RH5-34EM induced antibodies that were a thousand-fold more growth-inhibitory as a factor of PfRH5-specific antibody concentration. Finally, we show that priming with RH5-34EM and boosting with PfRH5 achieves the best balance between antibody quality and quantity and induces the most effective growth-inhibitory response. This rationally designed vaccine immunogen is now available for use as part of future malaria vaccines, alone or in combination with other immunogens.

目前迫切需要改进疟疾疫苗的免疫原。恶性疟原虫入侵红细胞对其生命周期、疾病症状和寄生虫传播至关重要。以 PfRH5 为靶点的抗体在阻止红细胞入侵方面非常有效,而且最有效的生长抑制抗体只与一个表位结合。在这里,我们使用结构引导方法设计了一种小型合成免疫原 RH5-34EM,它再现了这一表位。结构生物学和生物物理学证明,RH5-34EM 折叠正确,并能以纳摩尔级的亲和力与中和单克隆抗体结合。在免疫大鼠体内,RH5-34EM 能诱导抑制寄生虫生长的 PfRH5 靶向抗体。虽然 RH5-34EM 诱导的 PfRH5 特异性抗体浓度比 PfRH5 低,但 RH5-34EM 诱导的抗体对生长的抑制作用是 PfRH5 特异性抗体浓度的千倍。最后,我们表明,以 RH5-34EM 为底物,以 PfRH5 为增效剂,可以在抗体质量和数量之间达到最佳平衡,并诱导出最有效的生长抑制反应。这种经过合理设计的疫苗免疫原现在可以作为未来疟疾疫苗的一部分单独使用或与其他免疫原结合使用。
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引用次数: 0
The influence of AHR on immune and tissue biology. AHR 对免疫和组织生物学的影响。
IF 9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-01 Epub Date: 2024-09-06 DOI: 10.1038/s44321-024-00135-w
Brigitta Stockinger, Oscar E Diaz, Emma Wincent

The aryl hydrocarbon receptor is a ligand dependent transcription factor which functions as an environmental sensor. Originally discovered as the sensor for man made pollutants such as 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) it has recently gained prominence as an important mediator for environmental triggers via the diet or microbiota which influences many physiological functions in different cell types and tissues across the body. Notably AHR activity contributes to prevent excessive inflammation following tissue damage in barrier organs such as skin, lung or gut which has received wide attention in the past decade. In this review we will focus on emerging common AHR functions across cell types and tissues and discuss ongoing issues that confound the understanding of AHR physiology. Furthermore, we will discuss the need for deeper molecular understanding of the functional activity of AHR in different contexts with respect to development of potential therapeutic applications.

芳基烃受体是一种依赖配体的转录因子,具有环境传感器的功能。它最初是作为 2,3,7,8-四氯二苯并-对-二恶英(TCDD)等人造污染物的传感器而被发现的,最近,它作为通过饮食或微生物群影响全身不同细胞类型和组织中许多生理功能的环境触发器的重要介质而备受瞩目。值得注意的是,AHR 的活性有助于防止皮肤、肺部或肠道等屏障器官组织损伤后的过度炎症,这在过去十年中受到了广泛关注。在这篇综述中,我们将重点关注新出现的跨细胞类型和组织的 AHR 共同功能,并讨论目前阻碍人们了解 AHR 生理机能的问题。此外,我们还将讨论更深入地从分子角度了解 AHR 在不同情况下的功能活动的必要性,以开发潜在的治疗应用。
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引用次数: 0
Author Correction: SLC6A20 transporter: a novel regulator of brain glycine homeostasis and NMDAR function. 作者更正:SLC6A20 转运体:大脑甘氨酸平衡和 NMDAR 功能的新型调节器
IF 9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-01 DOI: 10.1038/s44321-024-00125-y
Mihyun Bae, Junyeop Daniel Roh, Youjoung Kim, Seong Soon Kim, Hye Min Han, Esther Yang, Hyojin Kang, Suho Lee, Jin Yong Kim, Ryeonghwa Kang, Hwajin Jung, Taesun Yoo, Hyosang Kim, Doyoun Kim, Heejeong Oh, Sungwook Han, Dayeon Kim, Jinju Han, Yong Chul Bae, Hyun Kim, Sunjoo Ahn, Andrew M Chan, Daeyoup Lee, Jin Woo Kim, Eunjoon Kim
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引用次数: 0
The evolving genetic landscape of telomere biology disorder dyskeratosis congenita. 端粒生物学疾病先天性角化障碍的基因演变。
IF 9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-01 Epub Date: 2024-08-28 DOI: 10.1038/s44321-024-00118-x
Hemanth Tummala, Amanda J Walne, Mohsin Badat, Manthan Patel, Abigail M Walne, Jenna Alnajar, Chi Ching Chow, Ibtehal Albursan, Jennifer M Frost, David Ballard, Sally Killick, Peter Szitányi, Anne M Kelly, Manoj Raghavan, Corrina Powell, Reinier Raymakers, Tony Todd, Elpis Mantadakis, Sophia Polychronopoulou, Nikolas Pontikos, Tianyi Liao, Pradeep Madapura, Upal Hossain, Tom Vulliamy, Inderjeet Dokal

Dyskeratosis congenita (DC) is a rare inherited bone marrow failure syndrome, caused by genetic mutations that principally affect telomere biology. Approximately 35% of cases remain uncharacterised at the genetic level. To explore the genetic landscape, we conducted genetic studies on a large collection of clinically diagnosed cases of DC as well as cases exhibiting features resembling DC, referred to as 'DC-like' (DCL). This led us to identify several novel pathogenic variants within known genetic loci and in the novel X-linked gene, POLA1. In addition, we have also identified several novel variants in POT1 and ZCCHC8 in multiple cases from different families expanding the allelic series of DC and DCL phenotypes. Functional characterisation of novel POLA1 and POT1 variants, revealed pathogenic effects on protein-protein interactions with primase, CTC1-STN1-TEN1 (CST) and shelterin subunit complexes, that are critical for telomere maintenance. ZCCHC8 variants demonstrated ZCCHC8 deficiency and signs of pervasive transcription, triggering inflammation in patients' blood. In conclusion, our studies expand the current genetic architecture and broaden our understanding of disease mechanisms underlying DC and DCL disorders.

先天性角化不良症(DC)是一种罕见的遗传性骨髓衰竭综合征,由主要影响端粒生物学的基因突变引起。大约 35% 的病例在基因水平上仍未定性。为了探索遗传特征,我们对大量临床诊断的DC病例以及表现出类似DC特征的病例(被称为 "类DC"(DCL))进行了遗传研究。这使我们在已知基因位点和新型 X 连锁基因 POLA1 中发现了几个新的致病变体。此外,我们还在不同家族的多个病例中发现了 POT1 和 ZCCHC8 的几个新型变体,从而扩大了 DC 和 DCL 表型的等位基因系列。对新型 POLA1 和 POT1 变体的功能特性分析表明,这些变体对与引物酶、CTC1-STN1-TEN1(CST)和庇护素亚基复合物的蛋白-蛋白相互作用有致病作用,而蛋白-蛋白相互作用对端粒的维持至关重要。ZCCHC8变体显示了ZCCHC8缺乏和普遍转录的迹象,引发了患者血液中的炎症。总之,我们的研究扩展了当前的遗传结构,并拓宽了我们对DC和DCL疾病机制的理解。
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引用次数: 0
7D, a small molecule inhibits dengue infection by increasing interferons and neutralizing-antibodies via CXCL4:CXCR3:p38:IRF3 and Sirt1:STAT3 axes respectively. 7D是一种小分子,可分别通过CXCL4:CXCR3:p38:IRF3和Sirt1:STAT3轴增加干扰素和中和抗体,从而抑制登革热感染。
IF 9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-01 Epub Date: 2024-09-16 DOI: 10.1038/s44321-024-00137-8
Kishan Kumar Gaur, Tejeswara Rao Asuru, Mitul Srivastava, Nitu Singh, Nikil Purushotham, Boja Poojary, Bhabatosh Das, Sankar Bhattacharyya, Shailendra Asthana, Prasenjit Guchhait

There are a limited number of effective vaccines against dengue virus (DENV) and significant efforts are being made to develop potent anti-virals. Previously, we described that platelet-chemokine CXCL4 negatively regulates interferon (IFN)-α/β synthesis and promotes DENV2 replication. An antagonist to CXCR3 (CXCL4 receptor) reversed it and inhibited viral replication. In a concurrent search, we identified CXCR3-antagonist from our compound library, namely 7D, which inhibited all serotypes of DENV in vitro. With a half-life of ~2.85 h in plasma and no significant toxicity, 7D supplementation (8 mg/kg-body-weight) to DENV2-infected IFNα/β/γR-/-AG129 or wild-type C57BL6 mice increased synthesis of IFN-α/β and IFN-λ, and rescued disease symptoms like thrombocytopenia, leukopenia and vascular-leakage, with improved survival. 7D, having the property to inhibit Sirt-1 deacetylase, promoted acetylation and phosphorylation of STAT3, which in-turn increased plasmablast proliferation, germinal-center maturation and synthesis of neutralizing-antibodies against DENV2 in mice. A STAT3-inhibitor successfully inhibited these effects of 7D. Together, these observations identify compound 7D as a stimulator of IFN-α/β/λ synthesis via CXCL4:CXCR3:p38:IRF3 signaling, and a booster for neutralizing-antibody generation by promoting STAT3-acetylation in plasmablasts, capable of protecting dengue infection.

目前针对登革热病毒(DENV)的有效疫苗数量有限,人们正在努力开发强效抗病毒药物。此前,我们曾描述过血小板趋化因子 CXCL4 负向调节干扰素(IFN)-α/β 的合成并促进 DENV2 的复制。CXCR3(CXCL4 受体)的拮抗剂可逆转这种作用并抑制病毒复制。在同时进行的搜索中,我们从化合物库中发现了 CXCR3 拮抗剂,即 7D,它能在体外抑制所有血清型的 DENV。7D在血浆中的半衰期约为2.85小时,且无明显毒性,给感染IFNα/β/γR-/-AG129或野生型C57BL6的DENV2小鼠补充7D(8毫克/千克体重)可增加IFN-α/β和IFN-λ的合成,缓解血小板减少、白细胞减少和血管渗漏等疾病症状,并提高存活率。7D 具有抑制 Sirt-1 去乙酰化酶的特性,可促进 STAT3 的乙酰化和磷酸化,进而增加小鼠浆细胞的增殖、生殖中心的成熟和抗 DENV2 中和抗体的合成。STAT3抑制剂成功抑制了7D的这些作用。总之,这些观察结果表明化合物 7D 可通过 CXCL4:CXCR3:p38:IRF3 信号刺激 IFN-α/β/λ 的合成,并通过促进血浆母细胞中 STAT3 的乙酰化促进中和抗体的生成,从而保护登革热感染。
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引用次数: 0
Author Correction: CBX3 antagonizes IFNγ/STAT1/PD-L1 axis to modulate colon inflammation and CRC chemosensitivity. 作者更正:CBX3 拮抗 IFNγ/STAT1/PD-L1 轴,调节结肠炎症和 CRC 化疗敏感性。
IF 9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-01 DOI: 10.1038/s44321-024-00141-y
Yao Xiang, Jorge Mata-Garrido, Yuanji Fu, Christophe Desterke, Eric Batsché, Ahmed Hamaï, Christine Sedlik, Youssouf Sereme, David Skurnik, Abdelali Jalil, Rachel Onifarasoaniaina, Eric Frapy, Jean-Christophe Beche, Razack Alao, Eliane Piaggio, Laurence Arbibe, Yunhua Chang
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引用次数: 0
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