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Biomedical researchers' perspectives on the reproducibility of research. 生物医学研究人员对研究可重复性的看法。
IF 9.8 1区 生物学 Q1 Agricultural and Biological Sciences Pub Date : 2024-11-05 eCollection Date: 2024-11-01 DOI: 10.1371/journal.pbio.3002870
Kelly D Cobey, Sanam Ebrahimzadeh, Matthew J Page, Robert T Thibault, Phi-Yen Nguyen, Farah Abu-Dalfa, David Moher

We conducted an international cross-sectional survey of biomedical researchers' perspectives on the reproducibility of research. This study builds on a widely cited 2016 survey on reproducibility and provides a biomedical-specific and contemporary perspective on reproducibility. To sample the community, we randomly selected 400 journals indexed in MEDLINE, from which we extracted the author names and emails from all articles published between October 1, 2020 and October 1, 2021. We invited participants to complete an anonymous online survey which collected basic demographic information, perceptions about a reproducibility crisis, perceived causes of irreproducibility of research results, experience conducting reproducibility studies, and knowledge of funding and training for research on reproducibility. A total of 1,924 participants accessed our survey, of which 1,630 provided useable responses (response rate 7% of 23,234). Key findings include that 72% of participants agreed there was a reproducibility crisis in biomedicine, with 27% of participants indicating the crisis was "significant." The leading perceived cause of irreproducibility was a "pressure to publish" with 62% of participants indicating it "always" or "very often" contributes. About half of the participants (54%) had run a replication of their own previously published study while slightly more (57%) had run a replication of another researcher's study. Just 16% of participants indicated their institution had established procedures to enhance the reproducibility of biomedical research and 67% felt their institution valued new research over replication studies. Participants also reported few opportunities to obtain funding to attempt to reproduce a study and 83% perceived it would be harder to do so than to get funding to do a novel study. Our results may be used to guide training and interventions to improve research reproducibility and to monitor rates of reproducibility over time. The findings are also relevant to policy makers and academic leadership looking to create incentives and research cultures that support reproducibility and value research quality.

我们针对生物医学研究人员对研究可重复性的看法开展了一项国际横断面调查。本研究以 2016 年一项被广泛引用的可重复性调查为基础,提供了生物医学特定的当代可重复性视角。为了对社区进行抽样调查,我们随机选择了 400 种被 MEDLINE 索引的期刊,从中提取了 2020 年 10 月 1 日至 2021 年 10 月 1 日期间发表的所有文章的作者姓名和电子邮件。我们邀请参与者完成匿名在线调查,调查内容包括基本人口统计学信息、对可重复性危机的看法、研究成果不可重复的原因、开展可重复性研究的经验以及对可重复性研究的资助和培训的了解。共有 1,924 名参与者参与了我们的调查,其中 1,630 人提供了可用的回复(回复率为 23,234 人的 7%)。主要发现包括:72%的参与者认为生物医学存在可重复性危机,27%的参与者表示危机 "严重"。造成不可再现性的主要原因是 "出版压力",62%的参与者表示 "总是 "或 "经常 "有这种压力。约有一半的参与者(54%)曾对自己以前发表的研究进行过复制,而对其他研究人员的研究进行过复制的参与者略多(57%)。仅有 16% 的参与者表示,他们所在的机构已经制定了提高生物医学研究可重复性的程序,67% 的参与者认为他们所在的机构重视新研究而非重复研究。参与者还报告说,他们很少有机会获得资金来尝试复制一项研究,83%的人认为这样做比获得资金进行一项新的研究要困难得多。我们的研究结果可用于指导培训和干预措施,以提高研究的可重复性,并随着时间的推移监测可重复性的比率。这些研究结果也与决策者和学术领导层有关,他们希望建立支持可重复性和重视研究质量的激励机制和研究文化。
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引用次数: 0
Apoptotic extracellular vesicles carrying Mif regulate macrophage recruitment and compensatory proliferation in neighboring epithelial stem cells during tissue maintenance. 在组织维持过程中,携带 Mif 的凋亡细胞外囊泡可调节巨噬细胞的招募和邻近上皮干细胞的代偿性增殖。
IF 9.8 1区 生物学 Q1 Agricultural and Biological Sciences Pub Date : 2024-11-04 eCollection Date: 2024-11-01 DOI: 10.1371/journal.pbio.3002194
Safia A Essien, Ivanshi Ahuja, George T Eisenhoffer

Apoptotic cells can signal to neighboring cells to stimulate proliferation and compensate for cell loss to maintain tissue homeostasis. While apoptotic cell-derived extracellular vesicles (AEVs) can transmit instructional cues to mediate communication with neighboring cells, the molecular mechanisms that induce cell division are not well understood. Here, we show that macrophage migration inhibitory factor (Mif)-containing AEVs regulate compensatory proliferation via ERK signaling in epithelial stem cells of larval zebrafish. Time-lapse imaging showed efferocytosis of AEVs from dying epithelial stem cells by healthy neighboring stem cells. Proteomic and ultrastructure analysis of purified AEVs identified Mif localization on the AEV surface. Pharmacological inhibition or genetic mutation of Mif, or its cognate receptor CD74, decreased levels of phosphorylated ERK and compensatory proliferation in the neighboring epithelial stem cells. Disruption of Mif activity also caused decreased numbers of macrophages patrolling near AEVs, while depletion of the macrophage lineage resulted in a reduced proliferative response by the epithelial stem cells. We propose that AEVs carrying Mif directly stimulate epithelial stem cell repopulation and guide macrophages to cell non-autonomously induce localized proliferation to sustain overall cell numbers during tissue maintenance.

凋亡细胞可向邻近细胞发出信号,以刺激细胞增殖并补偿细胞损失,从而维持组织的平衡。虽然凋亡细胞衍生的细胞外囊泡(AEVs)可以传递指令线索,介导与邻近细胞的交流,但诱导细胞分裂的分子机制还不十分清楚。在这里,我们发现含巨噬细胞迁移抑制因子(Mif)的AEV通过ERK信号调节幼体斑马鱼上皮干细胞的代偿性增殖。延时成像显示,健康的邻近干细胞会从濒死的上皮干细胞中排出AEVs。对纯化的AEV进行的蛋白质组学和超微结构分析确定了Mif在AEV表面的定位。药理抑制或基因突变Mif或其同源受体CD74,可降低磷酸化ERK的水平,并减少邻近上皮干细胞的代偿性增殖。Mif活性的破坏还导致在AEV附近巡逻的巨噬细胞数量减少,而巨噬细胞系的耗竭导致上皮干细胞的增殖反应减弱。我们认为,携带Mif的AEV可直接刺激上皮干细胞的重新填充,并引导巨噬细胞非自主地诱导局部增殖,以维持组织维持过程中的整体细胞数量。
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引用次数: 0
Climate and ecology predict latitudinal trends in sexual selection inferred from avian mating systems. 气候和生态学预测了从鸟类交配系统推断出的性选择的纬度趋势。
IF 9.8 1区 生物学 Q1 Agricultural and Biological Sciences Pub Date : 2024-11-04 eCollection Date: 2024-11-01 DOI: 10.1371/journal.pbio.3002856
Robert A Barber, Jingyi Yang, Chenyue Yang, Oonagh Barker, Tim Janicke, Joseph A Tobias

Sexual selection, one of the central pillars of evolutionary theory, has powerful effects on organismal morphology, behaviour, and population dynamics. However, current knowledge about geographical variation in this evolutionary mechanism and its underlying drivers remains highly incomplete, in part because standardised data on the strength of sexual selection is sparse even for well-studied organisms. Here, we use information on mating systems-including the incidence of polygamy and extra-pair paternity-to estimate the intensity of sexual selection in 10,671 (>99.9%) bird species distributed worldwide. We show that avian sexual selection varies latitudinally, peaking at higher latitudes, although the gradient is reversed in the world's most sexually selected birds-specialist frugivores-which are strongly associated with tropical forests. Phylogenetic models further reveal that the strength of sexual selection is explained by temperature seasonality coupled with a suite of climate-associated factors, including migration, diet, and territoriality. Overall, these analyses suggest that climatic conditions leading to short, intense breeding seasons, or highly abundant and patchy food resources, increase the potential for polygamy in birds, driving latitudinal gradients in sexual selection. Our findings help to resolve longstanding debates about spatial variation in evolutionary mechanisms linked to reproductive biology and also provide a comprehensive species-level data set for further studies of selection and phenotypic evolution in the context of global climatic change.

性选择是进化理论的核心支柱之一,对生物体的形态、行为和种群动态具有强大的影响。然而,目前对这一进化机制的地域差异及其内在驱动因素的了解还很不全面,部分原因是即使是对研究得很好的生物,有关性选择强度的标准化数据也很稀少。在这里,我们利用交配系统的信息--包括一夫多妻制和配对外父子关系的发生率--来估算分布在全球的 10671 种(>99.9%)鸟类的性选择强度。我们的研究表明,鸟类的性选择在纬度上各不相同,在高纬度地区达到顶峰,但在世界上性选择最强烈的鸟类--食俭鸟类--中,这种梯度是相反的,它们与热带森林密切相关。系统发生学模型进一步揭示了性选择的强度是由温度季节性和一系列气候相关因素(包括迁徙、饮食和领地性)共同解释的。总之,这些分析表明,导致短而密集的繁殖季节的气候条件,或高度丰富而分散的食物资源,增加了鸟类一夫多妻的可能性,推动了性选择的纬度梯度。我们的研究结果有助于解决长期以来关于与生殖生物学相关的进化机制的空间差异的争论,同时也为进一步研究全球气候变化背景下的选择和表型进化提供了全面的物种水平数据集。
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引用次数: 0
Amyloid accelerator polyphosphate fits as the mystery density in α-synuclein fibrils. 淀粉样加速剂多聚磷酸符合α-突触核蛋白纤维的神秘密度。
IF 9.8 1区 生物学 Q1 Agricultural and Biological Sciences Pub Date : 2024-10-31 eCollection Date: 2024-10-01 DOI: 10.1371/journal.pbio.3002650
Philipp Huettemann, Pavithra Mahadevan, Justine Lempart, Eric Tse, Budheswar Dehury, Brian F P Edwards, Daniel R Southworth, Bikash R Sahoo, Ursula Jakob

Aberrant aggregation of α-Synuclein is the pathological hallmark of a set of neurodegenerative diseases termed synucleinopathies. Recent advances in cryo-electron microscopy have led to the structural determination of the first synucleinopathy-derived α-Synuclein fibrils, which contain a non-proteinaceous, "mystery density" at the core of the protofilaments, hypothesized to be highly negatively charged. Guided by previous studies that demonstrated that polyphosphate (polyP), a universally conserved polyanion, significantly accelerates α-Synuclein fibril formation, we conducted blind docking and molecular dynamics simulation experiments to model the polyP binding site in α-Synuclein fibrils. Here, we demonstrate that our models uniformly place polyP into the lysine-rich pocket, which coordinates the mystery density in patient-derived fibrils. Subsequent in vitro studies and experiments in cells revealed that substitution of the 2 critical lysine residues K43 and K45 with alanine residues leads to a loss of all previously reported effects of polyP binding on α-Synuclein, including stimulation of fibril formation, change in filament conformation and stability as well as alleviation of cytotoxicity. In summary, our study demonstrates that polyP fits the unknown electron density present in in vivo α-Synuclein fibrils and suggests that polyP exerts its functions by neutralizing charge repulsion between neighboring lysine residues.

α-突触核蛋白的异常聚集是一系列被称为突触核蛋白病的神经退行性疾病的病理特征。冷冻电子显微镜技术的最新进展导致首次确定了源于突触核蛋白病的α-突触核蛋白纤维的结构。以前的研究表明,聚磷酸盐(polyP)--一种普遍保守的多阴离子--能显著加速α-突触核蛋白纤维的形成,在这些研究的指导下,我们进行了盲对接和分子动力学模拟实验,为α-突触核蛋白纤维中的polyP结合位点建模。在这里,我们证明了我们的模型能将 polyP 均匀地放入富含赖氨酸的口袋中,从而协调患者来源纤维中的神秘密度。随后的体外研究和细胞实验表明,用丙氨酸残基取代两个关键的赖氨酸残基 K43 和 K45 会导致先前报道的 polyP 结合对 α-Synuclein 的所有影响消失,包括刺激纤维形成、改变丝状构象和稳定性以及减轻细胞毒性。总之,我们的研究表明,polyP 符合体内α-突触核蛋白纤维中存在的未知电子密度,并表明 polyP 通过中和相邻赖氨酸残基之间的电荷排斥而发挥其功能。
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引用次数: 0
A multichannel electrophysiological approach to noninvasively and precisely record human spinal cord activity. 用多通道电生理方法无创、精确地记录人体脊髓活动。
IF 9.8 1区 生物学 Q1 Agricultural and Biological Sciences Pub Date : 2024-10-31 eCollection Date: 2024-10-01 DOI: 10.1371/journal.pbio.3002828
Birgit Nierula, Tilman Stephani, Emma Bailey, Merve Kaptan, Lisa-Marie Geertje Pohle, Ulrike Horn, André Mouraux, Burkhard Maess, Arno Villringer, Gabriel Curio, Vadim V Nikulin, Falk Eippert

The spinal cord is of fundamental importance for integrative processing in brain-body communication, yet routine noninvasive recordings in humans are hindered by vast methodological challenges. Here, we overcome these challenges by developing an easy-to-use electrophysiological approach based on high-density multichannel spinal recordings combined with multivariate spatial-filtering analyses. These advances enable a spatiotemporal characterization of spinal cord responses and demonstrate a sensitivity that permits assessing even single-trial responses. To furthermore enable the study of integrative processing along the neural processing hierarchy in somatosensation, we expand this approach by simultaneous peripheral, spinal, and cortical recordings and provide direct evidence that bottom-up integrative processing occurs already within the spinal cord and thus after the first synaptic relay in the central nervous system. Finally, we demonstrate the versatility of this approach by providing noninvasive recordings of nociceptive spinal cord responses during heat-pain stimulation. Beyond establishing a new window on human spinal cord function at millisecond timescale, this work provides the foundation to study brain-body communication in its entirety in health and disease.

脊髓对于脑-体交流中的综合处理具有根本性的重要意义,然而人类的常规无创记录却受到大量方法学挑战的阻碍。在这里,我们通过开发一种基于高密度多通道脊髓记录并结合多元空间滤波分析的易用电生理学方法来克服这些挑战。这些进展实现了脊髓反应的时空特征描述,并展示了评估单次试验反应的灵敏度。为了进一步研究躯体感觉中神经处理层次的整合处理,我们通过同时记录外周、脊髓和皮层来扩展这种方法,并提供了直接证据,证明自下而上的整合处理已经在脊髓中发生,因此是在中枢神经系统的第一次突触中继之后。最后,我们通过提供热痛刺激时脊髓痛觉反应的无创记录,证明了这种方法的多功能性。除了在毫秒级时间尺度上为人类脊髓功能建立一个新窗口外,这项工作还为研究健康和疾病中的整个脑体交流奠定了基础。
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引用次数: 0
Microglia cannibalism during neurodevelopment results in necroptotic cell death. 神经发育过程中的小胶质细胞食人行为会导致细胞坏死。
IF 9.8 1区 生物学 Q1 Agricultural and Biological Sciences Pub Date : 2024-10-31 eCollection Date: 2024-10-01 DOI: 10.1371/journal.pbio.3002869
F Chris Bennett, Mariko L Bennett

Clearance of dying neurons by microglia is critical to healthy neurodevelopment, but what else do microglia eat? A new study in PLOS Biology demonstrates that microglia not only eat neurons but each other, and that this "microglia cannibalism" causes necroptotic cell death.

小胶质细胞清除垂死的神经元对健康的神经发育至关重要,但小胶质细胞还吃什么呢?PLOS Biology》上的一项新研究表明,小胶质细胞不仅吃神经元,而且还互相吃,这种 "小胶质细胞食人 "会导致细胞坏死。
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引用次数: 0
Ortholog of autism candidate gene RBM27 regulates mitoribosomal assembly factor MALS-1 to protect against mitochondrial dysfunction and axon degeneration during neurodevelopment. 自闭症候选基因RBM27的直向同源物调控线粒体组装因子MALS-1,以防止神经发育过程中的线粒体功能障碍和轴突变性。
IF 9.8 1区 生物学 Q1 Agricultural and Biological Sciences Pub Date : 2024-10-31 eCollection Date: 2024-10-01 DOI: 10.1371/journal.pbio.3002876
Tamjid A Chowdhury, David A Luy, Garrett Scapellato, Dorian Farache, Amy S Y Lee, Christopher C Quinn

Mitochondrial dysfunction is thought to be a key component of neurodevelopmental disorders such as autism, intellectual disability, and attention-deficit hyperactivity disorder (ADHD). However, little is known about the molecular mechanisms that protect against mitochondrial dysfunction during neurodevelopment. Here, we address this question through the investigation of rbm-26, the Caenorhabditis elegans ortholog of the RBM27 autism candidate gene, which encodes an RNA-binding protein whose role in neurons is unknown. We report that RBM-26 (RBM26/27) protects against axonal defects by negatively regulating expression of the MALS-1 (MALSU1) mitoribosomal assembly factor. Autism-associated missense variants in RBM-26 cause a sharp decrease in RBM-26 protein expression along with defects in axon overlap and axon degeneration that occurs during larval development. Using a biochemical screen, we identified the mRNA for the MALS-1 mitoribosomal assembly factor as a binding partner for RBM-26. Loss of RBM-26 function causes a dramatic overexpression of mals-1 mRNA and MALS-1 protein. Moreover, genetic analysis indicates that this overexpression of MALS-1 is responsible for the mitochondrial and axon degeneration defects in rbm-26 mutants. These observations reveal a mechanism that regulates expression of a mitoribosomal assembly factor to protect against axon degeneration during neurodevelopment.

线粒体功能障碍被认为是自闭症、智力障碍和注意力缺陷多动障碍(ADHD)等神经发育障碍的关键因素。然而,人们对神经发育过程中保护线粒体功能障碍的分子机制知之甚少。在这里,我们通过研究 RBM27 自闭症候选基因的草履虫直向同源物 rbm-26(它编码一种 RNA 结合蛋白,在神经元中的作用尚不清楚)来解决这个问题。我们报告说,RBM-26(RBM26/27)通过负向调节MALS-1(MALSU1)mitoribosomal组装因子的表达来防止轴突缺陷。RBM-26中与自闭症相关的错义变体会导致RBM-26蛋白表达急剧下降,并在幼虫发育过程中出现轴突重叠和轴突变性的缺陷。通过生化筛选,我们确定了 MALS-1 mitoribosomal 组装因子的 mRNA 是 RBM-26 的结合伙伴。RBM-26 功能的缺失会导致 mals-1 mRNA 和 MALS-1 蛋白的显著过表达。此外,遗传分析表明,MALS-1的过度表达是导致rbm-26突变体线粒体和轴突变性缺陷的原因。这些观察结果揭示了一种在神经发育过程中调节线粒体组装因子表达以防止轴突退化的机制。
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引用次数: 0
Microglia cannibalism and efferocytosis leads to shorter lifespans of developmental microglia. 小胶质细胞食人和排泄导致发育期小胶质细胞寿命缩短
IF 9.8 1区 生物学 Q1 Agricultural and Biological Sciences Pub Date : 2024-10-30 eCollection Date: 2024-10-01 DOI: 10.1371/journal.pbio.3002819
Hannah Gordon, Zachary T Schafer, Cody J Smith

The overproduction of cells and subsequent production of debris is a universal principle of neurodevelopment. Here, we show an additional feature of the developing nervous system that causes neural debris-promoted by the sacrificial nature of embryonic microglia that irreversibly become phagocytic after clearing other neural debris. Described as long-lived, microglia colonize the embryonic brain and persist into adulthood. Using transgenic zebrafish to investigate the microglia debris during brain construction, we identified that unlike other neural cell types that die in developmental stages after they have expanded, necroptosis-dependent microglial debris is prevalent when microglia are expanding in the zebrafish brain. Time-lapse imaging of microglia demonstrates that this debris is cannibalized by other microglia. To investigate features that promote microglia death and cannibalism, we used time-lapse imaging and fate-mapping strategies to track the lifespan of individual developmental microglia. These approaches revealed that instead of embryonic microglia being long-lived cells that completely digest their phagocytic debris, once most developmental microglia in zebrafish become phagocytic they eventually die, including ones that are cannibalistic. These results establish a paradox-which we tested by increasing neural debris and manipulating phagocytosis-that once most microglia in the embryo become phagocytic, they die, create debris, and then are cannibalized by other microglia, resulting in more phagocytic microglia that are destined to die.

细胞的过度增殖和随后产生的碎片是神经发育的一个普遍原则。在这里,我们展示了神经系统发育过程中导致神经碎片产生的另一个特征--胚胎小胶质细胞在清除其他神经碎片后不可逆转地成为吞噬细胞,这种牺牲性质促进了神经碎片的产生。小胶质细胞被描述为长寿细胞,它们在胚胎大脑中定植并持续到成年。利用转基因斑马鱼研究大脑构建过程中的小胶质细胞碎片,我们发现与其他神经细胞类型在发育阶段扩张后死亡不同,依赖坏死的小胶质细胞碎片在小胶质细胞在斑马鱼大脑中扩张时非常普遍。小胶质细胞的延时成像显示,这些碎片被其他小胶质细胞吞噬。为了研究促进小胶质细胞死亡和吞噬的特征,我们使用延时成像和命运图谱策略来追踪单个发育期小胶质细胞的寿命。这些方法发现,胚胎期小胶质细胞并不是完全消化其吞噬碎片的长寿细胞,而是一旦斑马鱼的大多数发育期小胶质细胞具有吞噬能力,它们最终都会死亡,包括那些食人的小胶质细胞。这些结果建立了一个悖论--我们通过增加神经碎片和操纵吞噬作用对其进行了测试--一旦胚胎中的大多数小胶质细胞具有吞噬能力,它们就会死亡,产生碎片,然后被其他小胶质细胞吞噬,导致更多具有吞噬能力的小胶质细胞注定死亡。
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引用次数: 0
The promises and challenges of neurotechnology to improve human health and cognition. 神经技术在改善人类健康和认知方面的前景与挑战。
IF 9.8 1区 生物学 Q1 Agricultural and Biological Sciences Pub Date : 2024-10-30 eCollection Date: 2024-10-01 DOI: 10.1371/journal.pbio.3002903
Simon Hanslmayr

This PLOS Biology collection explores the present and possible futures of neurotechnology to improve human health and cognition, as well as the scientific, technological and ethical challenges they face.

这本《PLOS 生物学》文集探讨了神经技术在改善人类健康和认知方面的现状和可能的未来,以及它们所面临的科学、技术和伦理挑战。
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引用次数: 0
Can neurotechnology revolutionize cognitive enhancement? 神经技术能否彻底改变认知能力的提高?
IF 9.8 1区 生物学 Q1 Agricultural and Biological Sciences Pub Date : 2024-10-29 eCollection Date: 2024-10-01 DOI: 10.1371/journal.pbio.3002831
Ines R Violante, Prince Okyere

The development and implementation of neurotechnology for cognitive enhancement could spearhead a new wave of innovation in the information age. However, we argue here that this will only happen with a more fundamental understanding of human brain function.

开发和实施用于增强认知能力的神经技术可以引领信息时代的新一轮创新浪潮。然而,我们在此认为,只有从根本上了解人脑功能,才能实现这一目标。
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引用次数: 0
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