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Artificial Intelligence could 'crack the language of cancer and Alzheimer's'

#artificialintelligence

Powerful algorithms used by Netflix, Amazon and Facebook can'predict' the biological language of cancer and neurodegenerative diseases like Alzheimer's, scientists have found. Big data produced during decades of research was fed into a computer language model to see if artificial intelligence can make more advanced discoveries than humans. Academics based at St John's College, University of Cambridge, found the machine-learning technology could decipher the'biological language' of cancer, Alzheimer's, and other neurodegenerative diseases. Their ground-breaking study has been published in the scientific journal PNAS today and could be used in the future to'correct the grammatical mistakes inside cells that cause disease'. Professor Tuomas Knowles, lead author of the paper and a Fellow at St John's College, said: "Bringing machine-learning technology into research into neurodegenerative diseases and cancer is an absolute game-changer. Ultimately, the aim will be to use artificial intelligence to develop targeted drugs to dramatically ease symptoms or to prevent dementia happening at all."


The glassiness of hardening protein droplets

Science

In addition to dissolving in the watery cytosol, proteins can self-assemble into materials with different mechanical properties, such as solid filaments or soft gels, to facilitate various cellular functions. In the past decade, proteins have been shown to undergo liquid-liquid phase separation (LLPS) to form liquid droplets in which proteins are highly concentrated but are still dynamic and fluid ([ 1 ][1], [ 2 ][2]). Many cellular compartments, such as nucleoli and stress granules, are phase-separated droplets. Although some droplets remain liquid for function, others harden into a less dynamic state over time ([ 3 ][3], [ 4 ][4]). On page 1317 of this issue, Jawerth et al. ([ 5 ][5]) report that the hardening protein droplets are Maxwell glasses. These are Maxwell fluids that age like glasses in that viscosity increases with age, whereas the elasticity changes little over time (see the figure). There are many distinctive features of LLPS that can be functionally relevant, one of which is the liquid property of the resulting droplets. Droplet fluidity is vital for ensuring proper chemical reactions occurring within the compartment. Disrupting the liquid properties of the nucleolus, for example, alters ribosomal RNA biogenesis ([ 6 ][6]). In addition, droplet fusion can be used for force generation to organize cellular space, such as clustering genomic loci ([ 7 ][7], [ 8 ][8]) or bundling cytoskeleton filaments ([ 9 ][9]). However, condensed phases formed with LLPS are not simple liquids but have diverse and changing material properties and are collectively called biomolecular condensates ([ 1 ][1]). The dependence of droplet fluidity on environmental factors (such as salt concentration) and condensate composition (such as RNA-to-protein ratio) has been revealed in vitro, with active rheology measured with optical tweezers and passive rheology measured with microbeads ([ 10 ][10]–[ 12 ][11]). Reconstituted droplets also undergo aging and maturation; that is, their material properties change with time. Some condensates harden into a less dynamic state in which they do not fuse but stick together after collision, and the proteins rearrange less within them ([ 3 ][3], [ 4 ][4]). Hardened condensates might be functional in that they can inhibit some chemical reactions or provide structural rigidity. The hardening process can also be vital for creating different material properties needed in a multistep cellular process. For example, in centrosome condensate formation with the protein spindle-defective protein 5 (SPD-5), the initial dynamic liquid may allow rapid protein incorporation early in the cell cycle, whereas the hardened condensate may provide the centrosome with the rigidity required to resist microtubule-pulling forces during mitosis ([ 4 ][4]). ![Figure][12] Phases that proteins form Proteins dissolved in solution (middle square) can self-assemble into liquids, solids, and gels. Jawerth et al. report that proteins can also harden into a new phase, a Maxwell glass. Protein liquids and Maxwell glasses are easier to reverse (double arrows) than protein gels and solids (single arrows). GRAPHIC: C. BICKEL/ SCIENCE FROM H. ZHANG In addition to hardening, some aged droplets even nucleate protein aggregates, including amyloids that are linked to various diseases ([ 10 ][10], [ 13 ][13], [ 14 ][14]). Thus, organizing biochemistry through LLPS may come at the cost of promoting pathological protein aggregation. However, the ability to nucleate solids is also exploited to seed cytoskeleton filaments, including actin and microtubules, from liquid condensates that concentrate monomers ([ 9 ][9]). Not only do condensate material properties change with environment, composition, and time, different material properties also coexist in subcompartments of a single condensate such as the nucleolus ([ 15 ][15]). These examples highlight the numerous ways that various condensate material properties can be combined to achieve complex functionality. Jawerth et al. characterized the material properties of reconstituted protein condensates that harden over time by combining optical tweezer manipulation and microrheology. These hardening condensates behave like Maxwell fluids that have both viscous and elastic components present at all times. The elasticity of the Maxwell fluid changes little with age, indicating that hardening is not a gelation process in which molecules become cross-linked. However, the viscosity strongly increases with age, suggesting that the molecular dynamics are hindered by protein jamming within the liquid. Because this material exhibits the behavior of Maxwell fluid but ages like glass, the authors call it Maxwell glass. Agreeing with the rheological results, no substantial structural changes within hardening condensates were observed with cryo–electron microscopy. Condensate-size shrinkage and increased protein density within the condensate were observed with fluorescent microscopy. The origin of protein jamming and how it links to protein chemistry await to be determined but will be needed to understand why some condensates harden over time and others do not. Jawerth et al. followed the hardening of five different proteins [ Caenorhabditis elegans protein PGL-3 (guanyl-specific ribonuclease pgl-3) and mammalian proteins FUS (RNA-binding protein FUS), EWSR1 (RNA-binding protein EWS), DAZAP1 (DAZ-associated protein 1), and TAF15 (TATA-binding protein–associated factor 2N)] with fluorescence recovery after photobleaching and studied the rheology of PGL-3 and FUS with optical tweezer and microrheology methods. Future work could expand the rheological studies to other condensates. For example, porous meshwork in hardened Saccharomyces cerevisiae and Schizosaccharomyces pombe Sup35 condensates was observed with cryo–electron microscopy, which suggests that they could be gels ([ 3 ][3]). Rheology studies on hardening Sup35 condensates would help to determine whether and how they age differently from condensates reported in this study. Nevertheless, it can no longer be assumed that all nondynamic condensates are gels because they may be Maxwell glasses. Distinguishing glass-like and gel-like responses of hardened condensates is not only conceptually but functionally essential. Both gels and glasses can be structurally stable. Gel stiffness can be actively regulated by the degree of cross-linking and can be tailored to sustain different magnitudes of forces. A glass can act as a mechanical sensor, just like liquid droplets ([ 7 ][7]), because it can flow under stress. A jammed glass only allows small molecules to pass, whereas the larger pores of a gel permit diffusion of macromolecules such as proteins. However, glasses are more easily fluidized. A gel would be more desirable for a condensate where structure rigidity and chemical reactions are both needed, such as for centrosomes ([ 4 ][4]). A glass is suitable for slowing down all macromolecule movement through jamming and allowing small molecules to pass through and quickly fluidize the content when needed, such as for stress-sensing condensates ([ 3 ][3]). It will be exciting to see which nondynamic condensates in cells are gels and which ones are glasses, and how cells exploit their material properties for functions. However, unlike the in vitro results reported by Jawerth et al. , directly probing rheological properties of endogenous condensates remains technically challenging. Tools for forming de novo condensates in live cells in a controlled manner may be useful for engineering condensates suitable for optical tweezer manipulation or embedding microbeads to follow condensate rheology ([ 7 ][7], [ 8 ][8]). 1. [↵][16]1. S. F. Banani, 2. H. O. Lee, 3. A. A. Hyman, 4. M. K. Rosen , Nat. Rev. Mol. Cell Biol. 18, 285 (2017). [OpenUrl][17][CrossRef][18][PubMed][19] 2. [↵][20]1. Y. Shin, 2. C. P. Brangwynne , Science 357, eaaf4382 (2017). [OpenUrl][21][Abstract/FREE Full Text][22] 3. [↵][23]1. T. M. Franzmann et al ., Science 359, eaao5654 (2018). [OpenUrl][24][Abstract/FREE Full Text][25] 4. [↵][26]1. J. B. Woodruff et al ., Cell 169, 1066 (2017). [OpenUrl][27][CrossRef][28][PubMed][29] 5. [↵][30]1. L. Jawerth et al ., Science 370, 1317 (2020). [OpenUrl][31][Abstract/FREE Full Text][32] 6. [↵][33]1. L. Zhu et al ., Proc. Natl. Acad. Sci. U.S.A. 116, 17330 (2019). [OpenUrl][34][Abstract/FREE Full Text][35] 7. [↵][36]1. Y. Shin et al ., Cell 175, 1481 (2018). [OpenUrl][37][CrossRef][38][PubMed][39] 8. [↵][40]1. H. Zhang et al ., Mol. Biol. Cell 31, 2048 (2020). [OpenUrl][41][CrossRef][42][PubMed][43] 9. [↵][44]1. T. Wiegand, 2. A. A. Hyman , Emerg. Top. Life Sci. , 1 (2020). [OpenUrl][45] 10. [↵][46]1. H. Zhang et al ., Mol. Cell 60, 220 (2015). [OpenUrl][47][CrossRef][48][PubMed][49] 11. 1. S. Elbaum-Garfinkle et al ., Proc. Natl. Acad. Sci. U.S.A. 112, 7189 (2015). [OpenUrl][50][Abstract/FREE Full Text][51] 12. [↵][52]1. L. M. Jawerth et al ., Phys. Rev. Lett. 121, 258101 (2018). [OpenUrl][53][CrossRef][54][PubMed][55] 13. [↵][56]1. Y. Lin, 2. D. S. W. Protter, 3. M. K. Rosen, 4. R. Parker , Mol. Cell 60, 208 (2015). [OpenUrl][57][CrossRef][58][PubMed][59] 14. [↵][60]1. A. Patel et al ., Cell 162, 1066 (2015). [OpenUrl][61][CrossRef][62][PubMed][63] 15. [↵][64]1. M. Feric et al ., Cell 165, 1686 (2016). [OpenUrl][65][CrossRef][66][PubMed][67] Acknowledgments: This work was supported by the U.S. National Institutes of Health (1K22CA23763201). 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This human protein may unfurl toxic tangles in Alzheimer's disease

PBS NewsHour

Gene therapy that increases the levels of an enzyme called CyP40 can reduce toxic tangles of tau protein in a mouse model of Alzheimer's disease (right panel versus control condition in left panel). A human protein -- called CyP40 -- can untangle the neurodegenerative clumps that characterize Alzheimer's and Parkinson's diseases, scientists reported Tuesday in the journal PLoS Biology. The findings may guide new therapeutic avenues for these conditions. "We were surprised that CyP40 could disaggregate the tangles," Laura Blair, a biologist at the University of South Florida and senior author of the study, said because very few human proteins can take these clumps and undo them. In Alzheimer's and Parkinson's diseases, certain proteins in the brain stick together in toxic, knotted clumps that cause cognitive decline.


Experts excited by brain 'wonder-drug'

BBC News

Scientists hope they have found a drug to stop all neurodegenerative brain diseases, including dementia. In 2013, a UK Medical Research Council team stopped brain cells dying in an animal for the first time, creating headline news around the world. But the compound used was unsuitable for people, as it caused organ damage. Now two drugs have been found that should have the same protective effect on the brain and are already safely used in people. "It's really exciting," said Prof Giovanna Mallucci, from the MRC Toxicology Unit in Leicester.


Alzheimer's disease could one day be identified YEARS before symptoms appear

Daily Mail - Science & tech

Chemicals in blood have been discovered which could one day be used to test for Alzheimer's before a person develops symptoms. Academics developed a technique which is able to spot disease biomarkers which are created during neurodegeneration -- the breakdown of neurons in the brain -- which happens in the brains of Alzheimer's sufferers. Tiny spheres called liposomes were repurposed to latch onto the proteins in the blood of mice, in a process the researchers compared to fishing. Currently, Alzheimer's disease is diagnosed with brain scans after symptoms emerge. A genetic treatment has been developed that leads to fruit flies living as much as nine per cent longer.