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SARS-CoV-2 evolution in animals suggests mechanisms for rapid variant selection (2021)

Bashor, Laura ; Gagne, Roderick B. ; Bosco-Lauth, Angela M. ; [weitere]

National Academy of Sciences

In: PNAS - Proceedings of the National Academy of Sciences of the United States of America. 2021; 118(44): e2105253118. Published 2021 Oct 29. doi: 10.1073/pnas.2105253118.

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Publikationsdatum: 2021-10-29

Beschreibung: SARS-CoV-2 spillback from humans into domestic and wild animals has been well documented, and an accumulating number of studies illustrate that human-to-animal transmission is widespread in cats, mink, deer, and other species. Experimental inoculations of cats, mink, and ferrets have perpetuated transmission cycles. We sequenced full genomes of Vero cell–expanded SARS-CoV-2 inoculum and viruses recovered from cats (n = 6), dogs (n = 3), hamsters (n = 3), and a ferret (n = 1) following experimental exposure. Five nonsynonymous changes relative to the USA-WA1/2020 prototype strain were near fixation in the stock used for inoculation but had reverted to wild-type sequences at these sites in dogs, cats, and hamsters within 1- to 3-d postexposure. A total of 14 emergent variants (six in nonstructural genes, six in spike, and one each in orf8 and nucleocapsid) were detected in viruses recovered from animals. This included substitutions in spike residues H69, N501, and D614, which also vary in human lineages of concern. Even though a live virus was not cultured from dogs, substitutions in replicase genes were detected in amplified sequences. The rapid selection of SARS-CoV-2 variants in vitro and in vivo reveals residues with functional significance during host switching. These observations also illustrate the potential for spillback from animal hosts to accelerate the evolution of new viral lineages, findings of particular concern for dogs and cats living in households with COVID-19 patients. More generally, this glimpse into viral host switching reveals the unrealized rapidity and plasticity of viral evolution in experimental animal model systems.

Print ISSN: 0027-8424

Digitale ISSN: 1091-6490

Thema: Biologie , Medizin , Allgemeine Naturwissenschaft

Publiziert von National Academy of Sciences

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Accurate model of liquid–liquid phase behavior of intrinsically disordered proteins from optimization of single-chain properties (2021)

Tesei, Giulio ; Schulze, Thea K. ; Crehuet, Ramon ; [weitere]

National Academy of Sciences

In: PNAS - Proceedings of the National Academy of Sciences of the United States of America. 2021; 118(44): e2111696118. Published 2021 Oct 29. doi: 10.1073/pnas.2111696118.

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Publikationsdatum: 2021-10-29

Beschreibung: Many intrinsically disordered proteins (IDPs) may undergo liquid–liquid phase separation (LLPS) and participate in the formation of membraneless organelles in the cell, thereby contributing to the regulation and compartmentalization of intracellular biochemical reactions. The phase behavior of IDPs is sequence dependent, and its investigation through molecular simulations requires protein models that combine computational efficiency with an accurate description of intramolecular and intermolecular interactions. We developed a general coarse-grained model of IDPs, with residue-level detail, based on an extensive set of experimental data on single-chain properties. Ensemble-averaged experimental observables are predicted from molecular simulations, and a data-driven parameter-learning procedure is used to identify the residue-specific model parameters that minimize the discrepancy between predictions and experiments. The model accurately reproduces the experimentally observed conformational propensities of a set of IDPs. Through two-body as well as large-scale molecular simulations, we show that the optimization of the intramolecular interactions results in improved predictions of protein self-association and LLPS.

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Thema: Biologie , Medizin , Allgemeine Naturwissenschaft

Publiziert von National Academy of Sciences

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Mammalian sperm hyperactivation regulates navigation via physical boundaries and promotes pseudo-chemotaxis (2021)

Zaferani, Meisam ; Suarez, Susan S. ; Abbaspourrad, Alireza

National Academy of Sciences

In: PNAS - Proceedings of the National Academy of Sciences of the United States of America. 2021; 118(44): e2107500118. Published 2021 Oct 29. doi: 10.1073/pnas.2107500118.

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Publikationsdatum: 2021-10-29

Beschreibung: Mammalian sperm migration within the complex and dynamic environment of the female reproductive tract toward the fertilization site requires navigational mechanisms, through which sperm respond to the tract environment and maintain the appropriate swimming behavior. In the oviduct (fallopian tube), sperm undergo a process called “hyperactivation,” which involves switching from a nearly symmetrical, low-amplitude, and flagellar beating pattern to an asymmetrical, high-amplitude beating pattern that is required for fertilization in vivo. Here, exploring bovine sperm motion in high–aspect ratio microfluidic reservoirs as well as theoretical and computational modeling, we demonstrate that sperm hyperactivation, in response to pharmacological agonists, modulates sperm–sidewall interactions and thus navigation via physical boundaries. Prior to hyperactivation, sperm remained swimming along the sidewalls of the reservoirs; however, once hyperactivation caused the intrinsic curvature of sperm to exceed a critical value, swimming along the sidewalls was reduced. We further studied the effect of noise in the intrinsic curvature near the critical value and found that these nonthermal fluctuations yielded an interesting “Run–Stop” motion on the sidewall. Finally, we observed that hyperactivation produced a “pseudo-chemotaxis” behavior, in that sperm stayed longer within microfluidic chambers containing higher concentrations of hyperactivation agonists.

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Thema: Biologie , Medizin , Allgemeine Naturwissenschaft

Publiziert von National Academy of Sciences

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Fevers and the social costs of acute infection in wild vervet monkeys (2021)

McFarland, Richard ; Henzi, S. Peter ; Barrett, Louise ; [weitere]

National Academy of Sciences

In: PNAS - Proceedings of the National Academy of Sciences of the United States of America. 2021; 118(44): e2107881118. Published 2021 Oct 29. doi: 10.1073/pnas.2107881118.

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Publikationsdatum: 2021-10-29

Beschreibung: Fevers are considered an adaptive response by the host to infection. For gregarious animals, however, fever and the associated sickness behaviors may signal a temporary loss of capacity, offering other group members competitive opportunities. We implanted wild vervet monkeys (Chlorocebus pygerythrus) with miniature data loggers to obtain continuous measurements of core body temperature. We detected 128 fevers in 43 monkeys, totaling 776 fever-days over a 6-year period. Fevers were characterized by a persistent elevation in mean and minimum 24-h body temperature of at least 0.5 °C. Corresponding behavioral data indicated that febrile monkeys spent more time resting and less time feeding, consistent with the known sickness behaviors of lethargy and anorexia, respectively. We found no evidence that fevers influenced the time individuals spent socializing with conspecifics, suggesting social transmission of infection within a group is likely. Notably, febrile monkeys were targeted with twice as much aggression from their conspecifics and were six times more likely to become injured compared to afebrile monkeys. Our results suggest that sickness behavior, together with its agonistic consequences, can carry meaningful costs for highly gregarious mammals. The degree to which social factors modulate the welfare of infected animals is an important aspect to consider when attempting to understand the ecological implications of disease.

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Thema: Biologie , Medizin , Allgemeine Naturwissenschaft

Publiziert von National Academy of Sciences

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Demonstration of the role of cell wall homeostasis in Staphylococcus aureus growth and the action of bactericidal antibiotics (2021)

Salamaga, Bartłomiej ; Kong, Lingyuan ; Pasquina-Lemonche, Laia ; [weitere]

National Academy of Sciences

In: PNAS - Proceedings of the National Academy of Sciences of the United States of America. 2021; 118(44): e2106022118. Published 2021 Oct 29. doi: 10.1073/pnas.2106022118.

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Publikationsdatum: 2021-10-29

Beschreibung: Bacterial cell wall peptidoglycan is essential, maintaining both cellular integrity and morphology, in the face of internal turgor pressure. Peptidoglycan synthesis is important, as it is targeted by cell wall antibiotics, including methicillin and vancomycin. Here, we have used the major human pathogen Staphylococcus aureus to elucidate both the cell wall dynamic processes essential for growth (life) and the bactericidal effects of cell wall antibiotics (death) based on the principle of coordinated peptidoglycan synthesis and hydrolysis. The death of S. aureus due to depletion of the essential, two-component and positive regulatory system for peptidoglycan hydrolase activity (WalKR) is prevented by addition of otherwise bactericidal cell wall antibiotics, resulting in stasis. In contrast, cell wall antibiotics kill via the activity of peptidoglycan hydrolases in the absence of concomitant synthesis. Both methicillin and vancomycin treatment lead to the appearance of perforating holes throughout the cell wall due to peptidoglycan hydrolases. Methicillin alone also results in plasmolysis and misshapen septa with the involvement of the major peptidoglycan hydrolase Atl, a process that is inhibited by vancomycin. The bactericidal effect of vancomycin involves the peptidoglycan hydrolase SagB. In the presence of cell wall antibiotics, the inhibition of peptidoglycan hydrolase activity using the inhibitor complestatin results in reduced killing, while, conversely, the deregulation of hydrolase activity via loss of wall teichoic acids increases the death rate. For S. aureus, the independent regulation of cell wall synthesis and hydrolysis can lead to cell growth, death, or stasis, with implications for the development of new control regimes for this important pathogen.

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Thema: Biologie , Medizin , Allgemeine Naturwissenschaft

Publiziert von National Academy of Sciences

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Live agent preference and social action monitoring in the macaque mid-superior temporal sulcus region (2021)

Ninomiya, Taihei ; Noritake, Atsushi ; Isoda, Masaki

National Academy of Sciences

In: PNAS - Proceedings of the National Academy of Sciences of the United States of America. 2021; 118(44): e2109653118. Published 2021 Oct 29. doi: 10.1073/pnas.2109653118.

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Publikationsdatum: 2021-10-29

Beschreibung: Mentalizing, the ability to infer the mental states of others, is a cornerstone of adaptive social intelligence. While functional brain mapping of human mentalizing has progressed considerably, its evolutionary signature in nonhuman primates remains debated. The discovery that the middle part of the macaque superior temporal sulcus (mid-STS) region has a connectional fingerprint most similar to the human temporoparietal junction (TPJ)—a crucial node in the mentalizing network—raises the possibility that these cortical areas may also share basic functional properties associated with mentalizing. Here, we show that this is the case in aspects of a preference for live social interactions and in a theoretical framework of predictive coding. Macaque monkeys were trained to perform a turn-taking choice task with another real monkey partner sitting directly face-to-face or a filmed partner appearing in prerecorded videos. We found that about three-fourths of task-related mid-STS neurons exhibited agent-dependent activity, most responding selectively or preferentially to the partner’s action. At the population level, activities of these partner-type neurons were significantly greater under live-partner compared to video-recorded–partner task conditions. Furthermore, a subset of the partner-type neurons responded proactively when predictions about the partner’s action were violated. This prediction error coding was specific to the action domain; almost none of the neurons signaled error in the prediction of reward. The present findings highlight unique roles of the macaque mid-STS at the single-neuron level and further delineate its functional parallels with the human TPJ in social cognitive processes associated with mentalizing.

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Thema: Biologie , Medizin , Allgemeine Naturwissenschaft

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Phase separation in the outer membrane of Escherichia coli (2021)

Benn, Georgina ; Mikheyeva, Irina V. ; Inns, Patrick George ; [weitere]

National Academy of Sciences

In: PNAS - Proceedings of the National Academy of Sciences of the United States of America. 2021; 118(44): e2112237118. Published 2021 Oct 29. doi: 10.1073/pnas.2112237118.

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Publikationsdatum: 2021-10-29

Beschreibung: Gram-negative bacteria are surrounded by a protective outer membrane (OM) with phospholipids in its inner leaflet and lipopolysaccharides (LPS) in its outer leaflet. The OM is also populated with many β-barrel outer-membrane proteins (OMPs), some of which have been shown to cluster into supramolecular assemblies. However, it remains unknown how abundant OMPs are organized across the entire bacterial surface and how this relates to the lipids in the membrane. Here, we reveal how the OM is organized from molecular to cellular length scales, using atomic force microscopy to visualize the OM of live bacteria, including engineered Escherichia coli strains and complemented by specific labeling of abundant OMPs. We find that a predominant OMP in the E. coli OM, the porin OmpF, forms a near-static network across the surface, which is interspersed with barren patches of LPS that grow and merge with other patches during cell elongation. Embedded within the porin network is OmpA, which forms noncovalent interactions to the underlying cell wall. When the OM is destabilized by mislocalization of phospholipids to the outer leaflet, a new phase appears, correlating with bacterial sensitivity to harsh environments. We conclude that the OM is a mosaic of phase-separated LPS-rich and OMP-rich regions, the maintenance of which is essential to the integrity of the membrane and hence to the lifestyle of a gram-negative bacterium.

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Thema: Biologie , Medizin , Allgemeine Naturwissenschaft

Publiziert von National Academy of Sciences

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Serum apolipoprotein A-I depletion is causative to silica nanoparticles–induced cardiovascular damage (2021)

Liu, Xuting ; Wei, Wei ; Liu, Zixuan ; [weitere]

National Academy of Sciences

In: PNAS - Proceedings of the National Academy of Sciences of the United States of America. 2021; 118(44): e2108131118. Published 2021 Oct 29. doi: 10.1073/pnas.2108131118.

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Publikationsdatum: 2021-10-29

Beschreibung: The rapid development of nanotechnology has greatly benefited modern science and engineering and also led to an increased environmental exposure to nanoparticles (NPs). While recent research has established a correlation between the exposure of NPs and cardiovascular diseases, the intrinsic mechanisms of such a connection remain unclear. Inhaled NPs can penetrate the air–blood barrier from the lung to systemic circulation, thereby intruding the cardiovascular system and generating cardiotoxic effects. In this study, on-site cardiovascular damage was observed in mice upon respiratory exposure of silica nanoparticles (SiNPs), and the corresponding mechanism was investigated by focusing on the interaction of SiNPs and their encountered biomacromolecules en route. SiNPs were found to collect a significant amount of apolipoprotein A-I (Apo A-I) from the blood, in particular when the SiNPs were preadsorbed with pulmonary surfactants. While the adsorbed Apo A-I ameliorated the cytotoxic and proinflammatory effects of SiNPs, the protein was eliminated from the blood upon clearance of the NPs. However, supplementation of Apo A-I mimic peptide mitigated the atherosclerotic lesion induced by SiNPs. In addition, we found a further declined plasma Apo A-I level in clinical silicosis patients than coronary heart disease patients, suggesting clearance of SiNPs sequestered Apo A-I to compromise the coronal protein’s regular biological functions. Together, this study has provided evidence that the protein corona of SiNPs acquired in the blood depletes Apo A-I, a biomarker for prediction of cardiovascular diseases, which gives rise to unexpected toxic effects of the nanoparticles.

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Thema: Biologie , Medizin , Allgemeine Naturwissenschaft

Publiziert von National Academy of Sciences

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Kinetic proofreading of lipochitooligosaccharides determines signal activation of symbiotic plant receptors (2021)

Gysel, Kira ; Laursen, Mette ; Thygesen, Mikkel B. ; [weitere]

National Academy of Sciences

In: PNAS - Proceedings of the National Academy of Sciences of the United States of America. 2021; 118(44): e2111031118. Published 2021 Oct 29. doi: 10.1073/pnas.2111031118.

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Publikationsdatum: 2021-10-29

Beschreibung: Plants and animals use cell surface receptors to sense and interpret environmental signals. In legume symbiosis with nitrogen-fixing bacteria, the specific recognition of bacterial lipochitooligosaccharide (LCO) signals by single-pass transmembrane receptor kinases determines compatibility. Here, we determine the structural basis for LCO perception from the crystal structures of two lysin motif receptor ectodomains and identify a hydrophobic patch in the binding site essential for LCO recognition and symbiotic function. We show that the receptor monitors the composition of the amphiphilic LCO molecules and uses kinetic proofreading to control receptor activation and signaling specificity. We demonstrate engineering of the LCO binding site to fine-tune ligand selectivity and correct binding kinetics required for activation of symbiotic signaling in plants. Finally, the hydrophobic patch is found to be a conserved structural signature in this class of LCO receptors across legumes that can be used for in silico predictions. Our results provide insights into the mechanism of cell-surface receptor activation by kinetic proofreading of ligands and highlight the potential in receptor engineering to capture benefits in plant–microbe interactions.

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Thema: Biologie , Medizin , Allgemeine Naturwissenschaft

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MDM2, MDMX, and p73 regulate cell-cycle progression in the absence of wild-type p53 (2021)

Klein, Alyssa M. ; Biderman, Lynn ; Tong, David ; [weitere]

National Academy of Sciences

In: PNAS - Proceedings of the National Academy of Sciences of the United States of America. 2021; 118(44): e2102420118. Published 2021 Oct 29. doi: 10.1073/pnas.2102420118.

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Publikationsdatum: 2021-10-29

Beschreibung: The p53 tumor suppressor protein, known to be critically important in several processes including cell-cycle arrest and apoptosis, is highly regulated by multiple mechanisms, most certifiably the Murine Double Minute 2–Murine Double Minute X (MDM2–MDMX) heterodimer. The role of MDM2–MDMX in cell-cycle regulation through inhibition of p53 has been well established. Here we report that in cells either lacking p53 or expressing certain tumor-derived mutant forms of p53, loss of endogenous MDM2 or MDMX, or inhibition of E3 ligase activity of the heterocomplex, causes cell-cycle arrest. This arrest is correlated with a reduction in E2F1, E2F3, and p73 levels. Remarkably, direct ablation of endogenous p73 produces a similar effect on the cell cycle and the expression of certain E2F family members at both protein and messenger RNA levels. These data suggest that MDM2 and MDMX, working at least in part as a heterocomplex, may play a p53-independent role in maintaining cell-cycle progression by promoting the activity of E2F family members as well as p73, making them a potential target of interest in cancers lacking wild-type p53.

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Thema: Biologie , Medizin , Allgemeine Naturwissenschaft

Publiziert von National Academy of Sciences

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