Multifaceted roles of plant glycosyl hydrolases during pathogen infections: more to discover.

MAIN CONCLUSION: Carbohydrates are hydrolyzed by a family of carbohydrate-active enzymes (CAZymes) called glycosidases or glycosyl hydrolases. Here, we have summarized the roles of various plant defense glycosidases that possess different substrate specificities. We have also highlighted the open questions in this research field. Glycosidases or glycosyl hydrolases (GHs) are a family of carbohydrate-active enzymes (CAZymes) that hydrolyze glycosidic bonds in carbohydrates and glycoconjugates. Compared to those of all other sequenced organisms, plant genomes contain a remarkable diversity of glycosidases. Plant glycosidases exhibit activities on various substrates and have been shown to play important roles during pathogen infections. Plant glycosidases from different GH families have been shown to act upon pathogen components, host cell walls, host apoplastic sugars, host secondary metabolites, and host N-glycans to mediate immunity against invading pathogens. We could classify the activities of these plant defense GHs under eleven different mechanisms through which they operate during pathogen infections. Here, we have provided comprehensive information on the catalytic activities, GH family classification, subcellular localization, domain structure, functional roles, and microbial strategies to regulate the activities of defense-related plant GHs. We have also emphasized the research gaps and potential investigations needed to advance this topic of research.

Fusions of Consciousness.

What are conscious experiences? Can they combine to form new experiences? What are conscious subjects? Can they combine to form new subjects? Most attempts to answer these questions assume that spacetime, and some of its particles, are fundamental. However, physicists tell us that spacetime cannot be fundamental. Spacetime, they say, is doomed. We heed the physicists, and drop the assumption that spacetime is fundamental. We assume instead that subjects and experiences are entities beyond spacetime, not within spacetime. We make this precise in a mathematical theory of conscious agents, whose dynamics are described by Markov chains. We show how (1) agents combine into more complex agents, (2) agents fuse into simpler agents, and (3) qualia fuse to create new qualia. The possible dynamics of n agents form an n(n-1)-dimensional polytope with nn vertices-the Markov polytopeMn. The total fusions of n agents and qualia form an (n-1)-dimensional simplex-the fusion simplexFn. To project the Markovian dynamics of conscious agents onto scattering processes in spacetime, we define a new map from Markov chains to decorated permutations. Such permutations-along with helicities, or masses and spins-invariantly encode all physical information used to compute scattering amplitudes. We propose that spacetime and scattering processes are a data structure that codes for interactions of conscious agents: a particle in spacetime is a projection of the Markovian dynamics of a communicating class of conscious agents.

Structural-functional diversity of malaria parasite's PfHSP70-1 and PfHSP40 chaperone pair gives an edge over human orthologs in chaperone-assisted protein folding.

Plasmodium falciparum, the human malaria parasite harbors a metastable proteome which is vulnerable to proteotoxic stress conditions encountered during its lifecycle. How parasite's chaperone machinery is able to maintain its aggregation-prone proteome in functional state, is poorly understood. As HSP70-40 system forms the central hub in cellular proteostasis, we investigated the protein folding capacity of PfHSP70-1 and PfHSP40 chaperone pair and compared it with human orthologs (HSPA1A and DNAJA1). Despite the structural similarity, we observed that parasite chaperones and their human orthologs exhibit striking differences in conformational dynamics. Comprehensive biochemical investigations revealed that PfHSP70-1 and PfHSP40 chaperone pair has better protein folding, aggregation inhibition, oligomer remodeling and disaggregase activities than their human orthologs. Chaperone-swapping experiments suggest that PfHSP40 can also efficiently cooperate with human HSP70 to facilitate the folding of client-substrate. SPR-derived kinetic parameters reveal that PfHSP40 has higher binding affinity towards unfolded substrate than DNAJA1. Interestingly, the observed slow dissociation rate of PfHSP40-substrate interaction allows PfHSP40 to maintain the substrate in folding-competent state to minimize its misfolding. Structural investigation through small angle x-ray scattering gave insights into the conformational architecture of PfHSP70-1 (monomer), PfHSP40 (dimer) and their complex. Overall, our data suggest that the parasite has evolved functionally diverged and efficient chaperone machinery which allows the human malaria parasite to survive in hostile conditions. The distinct allosteric landscapes and interaction kinetics of plasmodial chaperones open avenues for the exploration of small-molecule based antimalarial interventions.

Fitness Beats Truth in the Evolution of Perception.

Does natural selection favor veridical percepts-those that accurately (if not exhaustively) depict objective reality? Perceptual and cognitive scientists standardly claim that it does. Here we formalize this claim using the tools of evolutionary game theory and Bayesian decision theory. We state and prove the "Fitness-Beats-Truth (FBT) Theorem" which shows that the claim is false: If one starts with the assumption that perception involves inference to states of the objective world, then the FBT Theorem shows that a strategy that simply seeks to maximize expected-fitness payoff, with no attempt to estimate the "true" world state, does consistently better. More precisely, the FBT Theorem provides a quantitative measure of the extent to which the fitness-only strategy dominates the truth strategy, and of how this dominance increases with the size of the perceptual space. The FBT Theorem supports the Interface Theory of Perception (e.g. Hoffman et al. in Psychon Bull Rev https://doi.org/10.3758/s13423-015-0890-8 , 2015), which proposes that our perceptual systems have evolved to provide a species-specific interface to guide adaptive behavior, and not to provide a veridical representation of objective reality.

Fact, Fiction, and Fitness.

A theory of consciousness, whatever else it may do, must address the structure of experience. Our perceptual experiences are richly structured. Simply seeing a red apple, swaying between green leaves on a stout tree, involves symmetries, geometries, orders, topologies, and algebras of events. Are these structures also present in the world, fully independent of their observation? Perceptual theorists of many persuasions-from computational to radical embodied-say yes: perception veridically presents to observers structures that exist in an observer-independent world; and it does so because natural selection shapes perceptual systems to be increasingly veridical. Here we study four structures: total orders, permutation groups, cyclic groups, and measurable spaces. We ask whether the payoff functions that drive evolution by natural selection are homomorphisms of these structures. We prove, in each case, that generically the answer is no: as the number of world states and payoff values go to infinity, the probability that a payoff function is a homomorphism goes to zero. We conclude that natural selection almost surely shapes perceptions of these structures to be non-veridical. This is consistent with the interface theory of perception, which claims that natural selection shapes perceptual systems not to provide veridical perceptions, but to serve as species-specific interfaces that guide adaptive behavior. Our results present a constraint for any theory of consciousness which assumes that structure in perceptual experience is shaped by natural selection.

Extra-ribosomal functions of Mtb RpsB in imparting stress resilience and drug tolerance to mycobacteria.

Emerging observations suggest that ribosomal proteins (RPs) play important extra-ribosomal roles in maintenance of cellular homeostasis. However, the mechanistic insights into these processes have not been extensively explored, especially in pathogenic bacteria. Here, we present our findings on potential extra-ribosomal functions of Mycobacterium tuberculosis (Mtb) RPs. We observed that Mtb RpsB and RpsQ are differentially localized to cell wall fraction in M. tuberculosis (H37Rv), while their M. smegmatis (Msm) homologs are primarily cytosolic. Cellular fractionation of ectopically expressed Mtb RPs in surrogate host (M. smegmatis) also shows their association with cell membrane/cell wall without any gross changes in cell morphology. M. smegmatis expressing Mtb RpsB exhibited altered redox homeostasis, decreased drug-induced ROS, reduced cell wall permeability and increased tolerance to various proteotoxic stress (oxidative stress, SDS and starvation). Mtb RpsB expression was also associated with increased resistance specifically towards Isoniazid, Ethionamide and Streptomycin. The enhanced drug tolerance was specific to Mtb RpsB and not observed upon ectopic expression of M. smegmatis homolog (Msm RpsB). Interestingly, C-terminus deletion in Mtb RpsB affected its localization and reversed the stress-resilient phenotypes. We also observed that M. tuberculosis (H37Rv) with upregulated RpsB levels had higher intracellular survival in macrophage. All these observations hint towards existence of moonlighting roles of Mtb RpsB in imparting stress resilience to mycobacteria. This work open avenues for further exploration of alternative pathways associated with fitness and drug tolerance in mycobacteria.

Probing the interface theory of perception: Reply to commentaries.

We propose that selection favors nonveridical perceptions that are tuned to fitness. Current textbooks assert, to the contrary, that perception is useful because, in the normal case, it is veridical. Intuition, both lay and expert, clearly sides with the textbooks. We thus expected that some commentators would reject our proposal and provide counterarguments that could stimulate a productive debate. We are pleased that several commentators did indeed rise to the occasion and have argued against our proposal. We are also pleased that several others found our proposal worth exploring and have offered ways to test it, develop it, and link it more deeply to the history of ideas in the science and philosophy of perception. To both groups of commentators: thank you. Point and counterpoint, backed by data and theory, is the essence of science. We hope that the exchange recorded here will advance the scientific understanding of perception and its evolution. In what follows, we respond to the commentaries in alphabetical order.

The Interface Theory of Perception.

Perception is a product of evolution. Our perceptual systems, like our limbs and livers, have been shaped by natural selection. The effects of selection on perception can be studied using evolutionary games and genetic algorithms. To this end, we define and classify perceptual strategies and allow them to compete in evolutionary games in a variety of worlds with a variety of fitness functions. We find that veridical perceptions--strategies tuned to the true structure of the world--are routinely dominated by nonveridical strategies tuned to fitness. Veridical perceptions escape extinction only if fitness varies monotonically with truth. Thus, a perceptual strategy favored by selection is best thought of not as a window on truth but as akin to a windows interface of a PC. Just as the color and shape of an icon for a text file do not entail that the text file itself has a color or shape, so also our perceptions of space-time and objects do not entail (by the Invention of Space-Time Theorem) that objective reality has the structure of space-time and objects. An interface serves to guide useful actions, not to resemble truth. Indeed, an interface hides the truth; for someone editing a paper or photo, seeing transistors and firmware is an irrelevant hindrance. For the perceptions of H. sapiens, space-time is the desktop and physical objects are the icons. Our perceptions of space-time and objects have been shaped by natural selection to hide the truth and guide adaptive behaviors. Perception is an adaptive interface.

Objects of consciousness.

Current models of visual perception typically assume that human vision estimates true properties of physical objects, properties that exist even if unperceived. However, recent studies of perceptual evolution, using evolutionary games and genetic algorithms, reveal that natural selection often drives true perceptions to extinction when they compete with perceptions tuned to fitness rather than truth: Perception guides adaptive behavior; it does not estimate a preexisting physical truth. Moreover, shifting from evolutionary biology to quantum physics, there is reason to disbelieve in preexisting physical truths: Certain interpretations of quantum theory deny that dynamical properties of physical objects have definite values when unobserved. In some of these interpretations the observer is fundamental, and wave functions are compendia of subjective probabilities, not preexisting elements of physical reality. These two considerations, from evolutionary biology and quantum physics, suggest that current models of object perception require fundamental reformulation. Here we begin such a reformulation, starting with a formal model of consciousness that we call a "conscious agent." We develop the dynamics of interacting conscious agents, and study how the perception of objects and space-time can emerge from such dynamics. We show that one particular object, the quantum free particle, has a wave function that is identical in form to the harmonic functions that characterize the asymptotic dynamics of conscious agents; particles are vibrations not of strings but of interacting conscious agents. This allows us to reinterpret physical properties such as position, momentum, and energy as properties of interacting conscious agents, rather than as preexisting physical truths. We sketch how this approach might extend to the perception of relativistic quantum objects, and to classical objects of macroscopic scale.

Characterization of cytochrome c folding intermediates induced by sucrose and phosphate.

Spectroscopic and calorimetric investigations of the folding of denatured cytochrome c in the presence of phosphate ion and sugar were carried out to understand subtle differences in the nature of induced conformation and folding energy landscape. Altered conformations of cyt c induced by sucrose and phosphate, with same absorbance wavelength maxima, exhibit lack of tertiary interactions in segment 70-85 and similar α-helical content. However, compactness, the exposure of the heme to solvent and the secondary structure content in the two conformations are different. Although downhill folding was observed for both conformations, extent of cooperativity is higher in case of phosphate-induced conformation.