The Energy Landscape, Folding Pathways and the Kinetics of a Knotted Protein

The folding pathway and rate coefficients of the folding of a knotted protein are calculated for a potential energy function with minimal energetic frustration. A kinetic transition network is constructed using the discrete path sampling approach, and the resulting potential energy surface is visualized by constructing disconnectivity graphs. Owing to topological constraints, the low-lying portion of the landscape consists of three distinct regions, corresponding to the native knotted state and to configurations where either the N- or C-terminus is not yet folded into the knot. The fastest folding pathways from denatured states exhibit early formation of the N-terminus portion of the knot and a rate-determining step where the C-terminus is incorporated. The low-lying minima with the N-terminus knotted and the C-terminus free therefore constitute an off-pathway intermediate for this model. The insertion of both the N- and C-termini into the knot occur late in the folding process, creating large energy barriers that are the rate limiting steps in the folding process. When compared to other protein folding proteins of a similar length, this system folds over six orders of magnitude more slowly.Comment: 19 page

Quantum gravitational corrections for spinning particles

We calculate the quantum corrections to the gauge-invariant gravitational potentials of spinning particles in flat space, induced by loops of both massive and massless matter fields of various types. While the corrections to the Newtonian potential induced by massless conformal matter for spinless particles are well-known, and the same corrections due to massless minimally coupled scalars [Class. Quant. Grav. 27 (2010) 245008], massless non-conformal scalars [Phys. Rev. D 87 (2013) 104027] and massive scalars, fermions and vector bosons [Phys. Rev. D 91 (2015) 064047] have been recently derived, spinning particles receive additional corrections which are the subject of the present work. We give both fully analytic results valid for all distances from the particle, and present numerical results as well as asymptotic expansions. At large distances from the particle, the corrections due to massive fields are exponentially suppressed in comparison to the corrections from massless fields, as one would expect. However, a surprising result of our analysis is that close to the particle itself, on distances comparable to the Compton wavelength of the massive fields running in the loops, these corrections can be enhanced with respect to the massless case

Strategic crossing of biomass and harvest index—source and sink—achieves genetic gains in wheat

To accelerate genetic gains in breeding, physiological trait (PT) characterization of candidate parents can help make more strategic crosses, increasing the probability of accumulating favorable alleles compared to crossing relatively uncharacterized lines. In this study, crosses were designed to complement “source” with “sink” traits, where at least one parent was selected for favorable expression of biomass and/or radiation use efficiency—source—and the other for sink-related traits like harvest-index, kernel weight and grains per spike. Female parents were selected from among genetic resources—including landraces and products of wide-crossing (i.e. synthetic wheat)—that had been evaluated in Mexico at high yield potential or under heat stress, while elite lines were used as males. Progeny of crosses were advanced to the F4 generation within Mexico, and F4-derived F5 and F6 generations were yield tested to populate four international nurseries, targeted to high yield environments (2nd and 3rd WYCYT) for yield potential, and heat stressed environments (2nd and 4th SATYN) for climate resilience, respectively. Each nursery was grown as multi-location yield trials. Genetic gains were achieved in both temperate and hot environments, with most new PT-derived lines expressing superior yield and biomass compared to local checks at almost all international sites. Furthermore, the tendency across all four nurseries indicated either the superiority of the best new PT lines compared with the CIMMYT elite checks, or the superiority of all new PT lines as a group compared with all checks, and in some cases, both. Results support—in a realistic breeding context—the hypothesis that yield and radiation use efficiency can be increased by improving source:sink balance, and validate the feasibility of incorporating exotic germplasm into mainstream breeding efforts to accelerate genetic gains for yield potential and climate resilience

Female Behaviour Drives Expression and Evolution of Gustatory Receptors in Butterflies

Secondary plant compounds are strong deterrents of insect oviposition and feeding, but may also be attractants for specialist herbivores. These insect-plant interactions are mediated by insect gustatory receptors (Grs) and olfactory receptors (Ors). An analysis of the reference genome of the butterfly Heliconius melpomene, which feeds on passion-flower vines (Passiflora spp.), together with whole-genome sequencing within the species and across the Heliconius phylogeny has permitted an unprecedented opportunity to study the patterns of gene duplication and copy-number variation (CNV) among these key sensory genes. We report in silico gene predictions of 73 Gr genes in the H. melpomene reference genome, including putative CO2, sugar, sugar alcohol, fructose, and bitter receptors. The majority of these Grs are the result of gene duplications since Heliconius shared a common ancestor with the monarch butterfly or the silkmoth. Among Grs but not Ors, CNVs are more common within species in those gene lineages that have also duplicated over this evolutionary time-scale, suggesting ongoing rapid gene family evolution. Deep sequencing (∼1 billion reads) of transcriptomes from proboscis and labial palps, antennae, and legs of adult H. melpomene males and females indicates that 67 of the predicted 73 Gr genes and 67 of the 70 predicted Or genes are expressed in these three tissues. Intriguingly, we find that one-third of all Grs show female-biased gene expression (n = 26) and nearly all of these (n = 21) are Heliconius-specific Grs. In fact, a significant excess of Grs that are expressed in female legs but not male legs are the result of recent gene duplication. This difference in Gr gene expression diversity between the sexes is accompanied by a striking sexual dimorphism in the abundance of gustatory sensilla on the forelegs of H. melpomene, suggesting that female oviposition behaviour drives the evolution of new gustatory receptors in butterfly genomes

Pathogens and host immunity in the ancient human oral cavity.

Calcified dental plaque (dental calculus) preserves for millennia and entraps biomolecules from all domains of life and viruses. We report the first, to our knowledge, high-resolution taxonomic and protein functional characterization of the ancient oral microbiome and demonstrate that the oral cavity has long served as a reservoir for bacteria implicated in both local and systemic disease. We characterize (i) the ancient oral microbiome in a diseased state, (ii) 40 opportunistic pathogens, (iii) ancient human-associated putative antibiotic resistance genes, (iv) a genome reconstruction of the periodontal pathogen Tannerella forsythia, (v) 239 bacterial and 43 human proteins, allowing confirmation of a long-term association between host immune factors, 'red complex' pathogens and periodontal disease, and (vi) DNA sequences matching dietary sources. Directly datable and nearly ubiquitous, dental calculus permits the simultaneous investigation of pathogen activity, host immunity and diet, thereby extending direct investigation of common diseases into the human evolutionary past

Rheumatoid arthritis: pathological mechanisms and modern pharmacologic therapies.

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease that primarily affects the lining of the synovial joints and is associated with progressive disability, premature death, and socioeconomic burdens. A better understanding of how the pathological mechanisms drive the deterioration of RA progress in individuals is urgently required in order to develop therapies that will effectively treat patients at each stage of the disease progress. Here we dissect the etiology and pathology at specific stages: (i) triggering, (ii) maturation, (iii) targeting, and (iv) fulminant stage, concomitant with hyperplastic synovium, cartilage damage, bone erosion, and systemic consequences. Modern pharmacologic therapies (including conventional, biological, and novel potential small molecule disease-modifying anti-rheumatic drugs) remain the mainstay of RA treatment and there has been significant progress toward achieving disease remission without joint deformity. Despite this, a significant proportion of RA patients do not effectively respond to the current therapies and thus new drugs are urgently required. This review discusses recent advances of our  understanding of RA pathogenesis, disease modifying drugs, and provides perspectives on next generation therapeutics for RA

What Do We Know About Neuropsychological Aspects Of Schizophrenia?

Application of a neuropsychological perspective to the study of schizophrenia has established a number of important facts about this disorder. Some of the key findings from the existing literature are that, while neurocognitive impairment is present in most, if not all, persons with schizophrenia, there is both substantial interpatient heterogeneity and remarkable within-patient stability of cognitive function over the long-term course of the illness. Such findings have contributed to the firm establishment of neurobiologic models of schizophrenia, and thereby help to reduce the social stigma that was sometimes associated with purely psychogenic models popular during parts of the 20th century. Neuropsychological studies in recent decades have established the primacy of cognitive functions over psychopathologic symptoms as determinants of functional capacity and independence in everyday functioning. Although the cognitive benefits of both conventional and even second generation antipsychotic medications appear marginal at best, recognition of the primacy of cognitive deficits as determinants of functional disability in schizophrenia has catalyzed recent efforts to develop targeted treatments for the cognitive deficits of this disorder. Despite these accomplishments, however, some issues remain to be resolved. Efforts to firmly establish the specific neurocognitive/neuropathologic systems responsible for schizophrenia remain elusive, as do efforts to definitively demonstrate the specific cognitive deficits underlying specific forms of functional impairment. Further progress may be fostered by recent initiatives to integrate neuropsychological studies with experimental neuroscience, perhaps leading to measures of deficits in cognitive processes more clearly associated with specific, identifiable brain systems