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1999 Janelia Publications

Showing 51-60 of 1999 results
07/01/21 | Biomolecular Condensates and Their Links to Cancer Progression.
Cai D, Liu Z, Lippincott-Schwartz J
Trends in Biochemical Sciences. 2021 Jul 01;46(7):535-549. doi: 10.1016/j.tibs.2021.01.002

Liquid-liquid phase separation (LLPS) has emerged in recent years as an important physicochemical process for organizing diverse processes within cells via the formation of membraneless organelles termed biomolecular condensates. Emerging evidence now suggests that the formation and regulation of biomolecular condensates are also intricately linked to cancer formation and progression. We review the most recent literature linking the existence and/or dissolution of biomolecular condensates to different hallmarks of cancer formation and progression. We then discuss the opportunities that this condensate perspective provides for cancer research and the development of novel therapeutic approaches, including the perturbation of condensates by small-molecule inhibitors.

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07/01/21 | Bursting potentiates the neuro-AI connection.
Sun W, Zhao X, Spruston N
Nature Neuroscience. 2021 Jul 01;24(7):905-6. doi: 10.1038/s41593-021-00844-2
07/01/21 | Efficient and adaptive sensory codes.
Młynarski WF, Hermundstad AM
Nature Neuroscience. 2021 Jul 01;24(7):998-1009. doi: 10.1038/s41593-021-00846-0

The ability to adapt to changes in stimulus statistics is a hallmark of sensory systems. Here, we developed a theoretical framework that can account for the dynamics of adaptation from an information processing perspective. We use this framework to optimize and analyze adaptive sensory codes, and we show that codes optimized for stationary environments can suffer from prolonged periods of poor performance when the environment changes. To mitigate the adversarial effects of these environmental changes, sensory systems must navigate tradeoffs between the ability to accurately encode incoming stimuli and the ability to rapidly detect and adapt to changes in the distribution of these stimuli. We derive families of codes that balance these objectives, and we demonstrate their close match to experimentally observed neural dynamics during mean and variance adaptation. Our results provide a unifying perspective on adaptation across a range of sensory systems, environments, and sensory tasks.

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07/01/21 | Hunger or thirst state uncertainty is resolved by outcome evaluation in medial prefrontal cortex to guide decision-making.
Eiselt A, Chen S, Chen J, Arnold J, Kim T, Pachitariu M, Sternson SM
Nature Neuroscience. 2021 Jul 01;24(7):907-912. doi: 10.1038/s41593-021-00850-4

Physiological need states direct decision-making toward re-establishing homeostasis. Using a two-alternative forced choice task for mice that models elements of human decisions, we found that varying hunger and thirst states caused need-inappropriate choices, such as food seeking when thirsty. These results show limits on interoceptive knowledge of hunger and thirst states to guide decision-making. Instead, need states were identified after food and water consumption by outcome evaluation, which depended on the medial prefrontal cortex.

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07/01/21 | Intracellular mRNA transport and localized translation.
Das S, Vera M, Gandin V, Singer RH, Tutucci E
Nature Reviews Molecular Cell Biology. 2021 Jul 1;22(7):483-504. doi: 10.1038/s41580-021-00356-8

Fine-tuning cellular physiology in response to intracellular and environmental cues requires precise temporal and spatial control of gene expression. High-resolution imaging technologies to detect mRNAs and their translation state have revealed that all living organisms localize mRNAs in subcellular compartments and create translation hotspots, enabling cells to tune gene expression locally. Therefore, mRNA localization is a conserved and integral part of gene expression regulation from prokaryotic to eukaryotic cells. In this Review, we discuss the mechanisms of mRNA transport and local mRNA translation across the kingdoms of life and at organellar, subcellular and multicellular resolution. We also discuss the properties of messenger ribonucleoprotein and higher order RNA granules and how they may influence mRNA transport and local protein synthesis. Finally, we summarize the technological developments that allow us to study mRNA localization and local translation through the simultaneous detection of mRNAs and proteins in single cells, mRNA and nascent protein single-molecule imaging, and bulk RNA and protein detection methods.

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07/01/21 | Single-cell imaging of genome organization and dynamics.
Xie L, Liu Z
Molecular Systems Biology. 2021 Jul 01;17(7):e9653. doi: 10.15252/msb.20209653

Probing the architecture, mechanism, and dynamics of genome folding is fundamental to our understanding of genome function in homeostasis and disease. Most chromosome conformation capture studies dissect the genome architecture with population- and time-averaged snapshots and thus have limited capabilities to reveal 3D nuclear organization and dynamics at the single-cell level. Here, we discuss emerging imaging techniques ranging from light microscopy to electron microscopy that enable investigation of genome folding and dynamics at high spatial and temporal resolution. Results from these studies complement genomic data, unveiling principles underlying the spatial arrangement of the genome and its potential functional links to diverse biological activities in the nucleus.

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06/22/21 | In vivo glucose imaging in multiple model organisms with an engineered single-wavelength sensor.
Keller JP, Marvin JS, Lacin H, Lemon WC, Shea J, Kim S, Lee RT, Koyama M, Keller PJ, Looger LL
Cell Reports. 2021 Jun 22;35(12):109284. doi: 10.1016/j.celrep.2021.109284

Glucose is arguably the most important molecule in metabolism, and its dysregulation underlies diabetes. We describe a family of single-wavelength genetically encoded glucose sensors with a high signal-to-noise ratio, fast kinetics, and affinities varying over four orders of magnitude (1 μM to 10 mM). The sensors allow mechanistic characterization of glucose transporters expressed in cultured cells with high spatial and temporal resolution. Imaging of neuron/glia co-cultures revealed ∼3-fold faster glucose changes in astrocytes. In larval Drosophila central nervous system explants, intracellular neuronal glucose fluxes suggested a rostro-caudal transport pathway in the ventral nerve cord neuropil. In zebrafish, expected glucose-related physiological sequelae of insulin and epinephrine treatments were directly visualized. Additionally, spontaneous muscle twitches induced glucose uptake in muscle, and sensory and pharmacological perturbations produced large changes in the brain. These sensors will enable rapid, high-resolution imaging of glucose influx, efflux, and metabolism in behaving animals.

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06/15/21 | A cerebellar-thalamocortical pathway drives behavioral context-dependent movement initiation.
Dacre J, Colligan M, Clarke T, Ammer JJ, Schiemann J, Chamosa-Pino V, Claudi F, Harston JA, Eleftheriou C, Pakan JM, Huang C, Hantman AW, Rochefort NL, Duguid I
Neuron. 2021 Jun 15;109(14):2326-2338. doi: 10.1016/j.neuron.2021.05.016

Executing learned motor behaviors often requires the transformation of sensory cues into patterns of motor commands that generate appropriately timed actions. The cerebellum and thalamus are two key areas involved in shaping cortical output and movement, but the contribution of a cerebellar-thalamocortical pathway to voluntary movement initiation remains poorly understood. Here, we investigated how an auditory "go cue" transforms thalamocortical activity patterns and how these changes relate to movement initiation. Population responses in dentate/interpositus-recipient regions of motor thalamus reflect a time-locked increase in activity immediately prior to movement initiation that is temporally uncoupled from the go cue, indicative of a fixed-latency feedforward motor timing signal. Blocking cerebellar or motor thalamic output suppresses movement initiation, while stimulation triggers movements in a behavioral context-dependent manner. Our findings show how cerebellar output, via the thalamus, shapes cortical activity patterns necessary for learned context-dependent movement initiation.

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06/11/21 | Alpha-1 adrenergic receptor antagonists to prevent hyperinflammation and death from lower respiratory tract infection.
Koenecke A, Powell M, Xiong R, Shen Z, Fischer N, Huq S, Khalafallah AM, Trevisan M, Sparen P, Carrero JJ, Nishimura A, Caffo B, Stuart EA, Bai R, Staedtke V, Thomas DL, Papadopoulos N, Kinzler KW, Vogelstein B, Zhou S, Bettegowda C, Konig MF, Mensh BD, Vogelstein JT, Athey S
eLife. 2021 Jun 11;10:. doi: 10.7554/eLife.61700

In severe viral pneumonia, including Coronavirus disease 2019 (COVID-19), the viral replication phase is often followed by hyperinflammation, which can lead to acute respiratory distress syndrome, multi-organ failure, and death. We previously demonstrated that alpha-1 adrenergic receptor (⍺-AR) antagonists can prevent hyperinflammation and death in mice. Here, we conducted retrospective analyses in two cohorts of patients with acute respiratory distress (ARD, n = 18,547) and three cohorts with pneumonia (n = 400,907). Federated across two ARD cohorts, we find that patients exposed to ⍺-AR antagonists, as compared to unexposed patients, had a 34% relative risk reduction for mechanical ventilation and death (OR = 0.70, p = 0.021). We replicated these methods on three pneumonia cohorts, all with similar effects on both outcomes. All results were robust to sensitivity analyses. These results highlight the urgent need for prospective trials testing whether prophylactic use of ⍺-AR antagonists ameliorates lower respiratory tract infection-associated hyperinflammation and death, as observed in COVID-19.

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06/11/21 | Locating Macromolecular Assemblies in Cells by 2D Template Matching with TEM.
Lucas BA, Himes BA, Xue L, Grant T, Mahamid J, Grigorieff N
eLife. 2021 Jun 11;10:. doi: 10.7554/eLife.68946

For a more complete understanding of molecular mechanisms, it is important to study macromolecules and their assemblies in the broader context of the cell. This context can be visualized at nanometer resolution in three dimensions (3D) using electron cryo-tomography, which requires tilt series to be recorded and computationally aligned, currently limiting throughput. Additionally, the high-resolution signal preserved in the raw tomograms is currently limited by a number of technical difficulties, leading to an increased false-positive detection rate when using 3D template matching to find molecular complexes in tomograms. We have recently described a 2D template matching approach that addresses these issues by including high-resolution signal preserved in single-tilt images. A current limitation of this approach is the high computational cost that limits throughput. We describe here a GPU-accelerated implementation of 2D template matching in the image processing software TEM that allows for easy scaling and improves the accessibility of this approach. We apply 2D template matching to identify ribosomes in images of frozen-hydrated cells with high precision and sensitivity, demonstrating that this is a versatile tool for visual proteomics and structure determination. We benchmark the results with 3D template matching of tomograms acquired on identical sample locations and identify strengths and weaknesses of both techniques, which offer complementary information about target localization and identity.

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