Structure-based protein design with deep learning

Since the first revelation of proteins functioning as macromolecular machines through their three dimensional structures, researchers have been intrigued by the marvelous ways the biochemical processes are carried out by proteins. The aspiration to understand protein structures has fueled extensive efforts across different scientific disciplines. In recent years, it has been demonstrated that proteins with new functionality or shapes can be designed via structure-based modeling methods, and the design strategies have combined all available information — but largely piece-by-piece — from sequence derived statistics to the detailed atomic-level modeling of chemical interactions. Despite the significant progress, incorporating data-derived approaches through the use of deep learning methods can be a game changer. In this review, we summarize current progress, compare the arc of developing the deep learning approaches with the conventional methods, and describe the motivation and concepts behind current strategies that may lead to potential future opportunities.     

Changes in plant species richness and productivity in response to decreased nitrogen inputs in grassland in southern England

Biomass production and plant species diversity in grassland in southern England was monitored before and after a change from conventional to organic farming. Our 18-year study, part of the UK's Environmental Change Network long-term monitoring programme, showed that the cessation of artificial fertiliser use on grassland after conversion to organic farming resulted in a decrease in biomass production and an increase in plant species richness. Grassland productivity decreased immediately after fertiliser application ceased, and after two years the annual total biomass production had fallen by over 50%. In the subsequent decade, total annual grassland productivity did not change significantly, and yields reached 31–66% of the levels recorded pre-management change. Plant species richness that had remained stable during the first 5 years of our study under conventional farming, increased by 300% over the following 13 years under organic farm management. We suggest that the change in productivity is due to the altered composition of species within the plots. In the first few years after the change in farming practice, high yielding, nitrogen-loving plants were outcompeted by lower yielding grasses and forbs, and these species remained in the plots in the following years. This study shows that grassland can be converted from an environment lacking in plant species diversity to a relatively species-rich pasture within 10–15 years, simply by stopping or suspending nitrogen additions. We demonstrate that the trade-off for increasing species richness is a decrease in productivity. Grassland in the UK is often not only managed from a conservation perspective, but to also produce a profitable yield. By considering the species composition and encouraging specific beneficial species such as legumes, it may be possible to improve biomass productivity and reduce the trade-off.     

New directions in craniofacial morphogenesis

The vertebrate head is an extremely complicated structure: development of the head requires tissue-tissue interactions between derivates of all the germ layers and coordinated morphogenetic movements in three dimensions. In this review, we highlight a number of recent embryological studies, using chicken, frog, zebrafish and mouse, which have identified crucial signaling centers in the embryonic face. These studies demonstrate how small variations in growth factor signaling can lead to a diversity of phenotypic outcomes. We also discuss novel genetic studies, in human, mouse and zebrafish, which describe cell biological mechanisms fundamental to the growth and morphogenesis of the craniofacial skeleton. Together, these findings underscore the complex interactions leading to species-specific morphology. These and future studies will improve our understanding of the genetic and environmental influences underlying human craniofacial anomalies.     

Mechanisms of madness: evolutionary psychiatry without evolutionary psychology

Delusions are currently characterised as false beliefs produced by incorrect inference about external reality (DSM IV). This inferential conception has proved hard to link to explanations pitched at the level of neurobiology and neuroanatomy. This paper provides that link via a neurocomputational theory, based on evolutionary considerations, of the role of the prefrontal cortex in regulating offline cognition. When pathologically neuromodulated the prefrontal cortex produces hypersalient experiences which monopolise offline cognition. The result is characteristic psychotic experiences and patterns of thought. This bottom-up account uses neural network theory to integrate recent theories of the role of dopamine in delusion with the insights of inferential accounts. It also provides a general model for evolutionary psychiatry which avoids theoretical problems imported from evolutionary psychology.     

Fish community response to the longitudinal environmental gradient in Czech deep-valley reservoirs: Implications for ecological monitoring and management

Ecological quality assessment of non-natural water bodies is, in contrast to natural systems, less developed and requires determining biological indicators that reliably reflect environmental conditions and anthropogenic pressures. This study was motivated to propose fish indicators appropriate for assessment of reservoir ecosystems in central Europe. We analysed changes in water quality, total biomass and the taxonomic, trophic and size composition of fish communities along the longitudinal axes of four elongated, deep-valley reservoirs. Due to high nutrient inputs from their catchments, the reservoirs exhibited pronounced within-system gradients in primary productivity and water transparency. Although fish communities were similar among the reservoirs and dominated by few native species, the community structure and biomass systematically changed along the longitudinal axes of the reservoirs. The biomass and proportion of planktivores/benthivores in the fish community were highest at eutrophic sites near the river inflow and declined substantially towards deep, more oligotrophic sites close to the dam. The biomass and proportion of piscivores significantly increased downstream within the reservoirs alongside improving water quality. At species level, perch Perca fluviatilis and bream Abramis brama responded most sensitively, although in opposite directions, to the longitudinal environmental gradient. The major longitudinal changes in fish community characteristics were found to be consistent between pelagic and benthic habitats. The results of this study suggest that fish communities are appropriate indicators of eutrophication and can be used for ecological quality assessment of non-natural lentic water bodies, such as reservoirs. Moreover, our results underline the necessity to consider within-system gradients in water quality and the fish community when planning sampling programmes for deep-valley reservoirs.     

EXPERIMENTAL EVOLUTION OF RESISTANCE IN BRASSICA RAPA: CORRELATED RESPONSE OF TOLERANCE IN LINES SELECTED FOR GLUCOSINOLATE CONTENT

The evolutionary response of plant populations to selection for increased defense may be constrained by costs of defense. The purpose of this study was to investigate such constraints on the evolution of defense due to a cost of defense manifested as a trade-off between defense and tolerance. Variation in the response to artificial damage (tolerance) among lines of Brassica rapa that had been artificially selected for foliar glucosinolate content (defense) was examined. Leaf area was removed from replicates of three selection lines (high glucosinolates, control, and low glucosinolates) at three damage levels (0%, 20%, and 60% damage). An external cost of defense would result in a statistically significant selection line by damage treatment interaction, with those selected for high defense expressing less tolerance than those selected for low defense. Damage treatment had a significant overall effect on estimated total fitness, with fitness declining with increasing damage level. Further, selection line also had a significant overall effect on estimated total fitness, with low-defense selection lines having higher fitness compared to both control and high-defense selection lines. More importantly, a cost of defense in terms of tolerance was demonstrated by a significant selection line-by-damage treatment interaction. This interaction was in the direction to demonstrate a genetic trade-off between defense and tolerance, with low-defense selection lines decreasing estimated total fitness in response to damage less than both control and high-defense selection lines. Variation in tolerance among selection lines was due to the greater ability of low-defense lines to maintain fruit and seed production despite the presence of damage. In terms of tolerance, this cost of glucosinolate production in B. rapa could constrain the evolution of increased defense and, in so doing, maintain individuals within the population that are poorly defended yet tolerant.     

Structural variability of C3larvin toxin. Intrinsic dynamics of the α/β fold of the C3-like group of mono-ADP-ribosyltransferase toxins

C3larvin toxin is a new member of the C3 class of the mono-ADP-ribosyltransferase toxin family. The C3 toxins are known to covalently modify small G-proteins, e.g. RhoA, impairing their function, and serving as virulence factors for an offending pathogen. A full-length X-ray structure of C3larvin (2.3 Å) revealed that the characteristic mixed α/β fold consists of a central β-core flanked by two helical regions. Topologically, the protein can be separated into N and C lobes, each formed by a β-sheet and an α-motif, and connected by exposed loops involved in the recognition, binding, and catalysis of the toxin/enzyme, i.e. the ADP-ribosylation turn–turn and phosphate–nicotinamide PN loops. Herein, we provide two new C3larvin X-ray structures and present a systematic study of the toxin dynamics by first analyzing the experimental variability of the X-ray data-set followed by contrasting those results with theoretical predictions based on Elastic Network Models (GNM and ANM). We identify residues that participate in the stability of the N-lobe, putative hinges at loop residues, and energy-favored deformation vectors compatible with conformational changes of the key loops and 3D-subdomains (N/C-lobes), among the X-ray structures. We analyze a larger ensemble of known C3bot1 conformations and conclude that the characteristic ‘crab-claw’ movement may be driven by the main intrinsic modes of motion. Finally, via computational simulations, we identify harmonic and anharmonic fluctuations that might define the C3larvin ‘native state.’ Implications for docking protocols are derived.     

Delayed inducible resistance against a leaf-chewing insect in four deciduous tree species

Summary Both mechanical damage to mountain birch foliage and rearing of moth larvae on the trees reduced the growth of Epirrita autumnata larvae reared on these trees in the following year. The effects of physical damage and some other cues from insects were additive. On bird cherry the performance of Epirrita larvae was equal on untreated trees and on trees artificially defoliated in the previous year, but larval growth was reduced on previously insect-damaged branches. With mountain ash just physical damage per se reduced the performance of Epirrita larvae. On Salix phylicifolia there were no significant differences in the growth or survival of Epirrita on untreated control bushes and on bushes with partial larval damage during the previous year. Among untreated control trees the growth and survivorship of Epirrita were higher on fast-growing willow and bird cherry than on the slow-growing mountain birch. Mountain birch and mountain ash, the two deciduous tree species adapted to nutrient-poor soils, showed delayed inducible resistance triggered by defoliation (artificial or insect-made). This supports the hypothesis that delayed inducible resistance may be a passive response due to nutrient-stress caused by defoliation. On the other hand, the additional increase in the resistance of mountain birch triggered by specific cues from insects suggests that this response may be an evolved defense against leaf-eating insects.     

Binding of anti-fibronectin to early amphibian ectoderm does not result in inhibition of neural induction under in vitro conditions

Summary Antibodies directed to fibronectin (anti-FN) were injected into the blastocoel of late blastulae of Xenopus laevis. Two animal caps (ectoderm) were isolated, when control embryos reached the early gastrula stage, and were combined with untreated upper blastopore lip in the sandwich method. In two control series fibronectin or Holtfreter solution was injected into the blastocoel. The results of the experiments suggest that neural induction cannot be prevented by binding anti-FN to fibronectin, which covers the blastocoelic side of the ectoderm. The data support the view that extracellular matrix proteins are not themselves responsible for neural induction. However, in comparison with the control series a slight shift of the differentiation pattern in the spinocaudal direction could be observed in the anti-FN series. The possible role of extracellular proteins in the formation of a close juxtaposition of mesodermal and ectodermal target cells as a prerequisite for shortdistance transmission of neural inducers is discussed.     

Artificial seeds in barley: encapsulation of microspore-derived embryos

Summary An in vitro culture system has been developed for barley (Hordeum vulgare), which yields high frequencies of high quality microspore-derived embryos without an intervening callus phase. The embryos are very similar to zygotic embryos with regard to their morphology and germination capacity. These embryos were encapsulated in sodium alginate to produce individual beads containing one embryo each. In accordance with the literature, these beads are denoted artificial seeds. The artificial seeds germinated well and with a root system superior to that of non-encapsulated embryos. The artificial seeds also maintained their germination capacity for at least 6 months, whereas non-encapsulated embryos did not survive more than 2 weeks in storage. Artificial seeds, thus, probably provide a simple and universal delivery system of in vitro plantlets to greenhouse or field.