Signatures of arithmetic simplicity in metabolic network architecture

Metabolic networks perform some of the most fundamental functions in living cells, including energy transduction and building block biosynthesis. While these are the best characterized networks in living systems, understanding their evolutionary history and complex wiring constitutes one of the most fascinating open questions in biology, intimately related to the enigma of life's origin itself. Is the evolution of metabolism subject to general principles, beyond the unpredictable accumulation of multiple historical accidents? Here we search for such principles by applying to an artificial chemical universe some of the methodologies developed for the study of genome scale models of cellular metabolism. In particular, we use metabolic flux constraint-based models to exhaustively search for artificial chemistry pathways that can optimally perform an array of elementary metabolic functions. Despite the simplicity of the model employed, we find that the ensuing pathways display a surprisingly rich set of properties, including the existence of autocatalytic cycles and hierarchical modules, the appearance of universally preferable metabolites and reactions, and a logarithmic trend of pathway length as a function of input/output molecule size. Some of these properties can be derived analytically, borrowing methods previously used in cryptography. In addition, by mapping biochemical networks onto a simplified carbon atom reaction backbone, we find that several of the properties predicted by the artificial chemistry model hold for real metabolic networks. These findings suggest that optimality principles and arithmetic simplicity might lie beneath some aspects of biochemical complexity

Self-reported sex differences in high-functioning adults with autism: a meta-analysis

Background: Sex differences in autistic symptomatology are believed to contribute to the mis- and missed diagnosis of many girls and women with an autism spectrum condition (ASC). Whilst recent years have seen the emergence of clinical and empirical reports delineating the profile of young autistic girls, recognition of sex differences in symptomatology in adulthood is far more limited. Methods: We chose here to focus on symptomatology as reported using a screening instrument, the Ritvo Autism Asperger Diagnostic Scale-Revised (RAADS-R). In a meta-analysis, we pooled and analysed RAADS-R data from a number of experimental groups. Analysis of variance (ANOVA) searched for the presence of main effects of Sex and Diagnosis and for interactions between these factors in our sample of autistic and non-autistic adults. Results: In social relatedness and circumscribed interests, main effects of Diagnosis revealed that as expected, autistic adults reported significantly greater lifetime prevalence of symptoms in these domains; an effect of Sex, in circumscribed interests, also suggested that males generally reported more prevalent symptoms than females. An interaction of Sex and Diagnosis in language symptomatology revealed that a normative sex difference in language difficulties was attenuated in autism. An interaction of Sex and Diagnosis in the sensorimotor domain revealed the opposite picture: a lack of sex differences between typically-developing men and women and a greater prevalence of sensorimotor symptoms in autistic women than autistic men. Conclusions: We discuss the literature on childhood sex differences in relation to those which emerged in our adult sample. Where childhood sex differences fail to persist in adulthood, several interpretations exist, and we discuss, for example, an inherent sampling bias that may mean that only autistic women most similar to the male presentation are diagnosed. The finding that sensorimotor symptomatology is more highly reported by autistic women is a finding requiring objective confirmation, given its potential importance in diagnosis

Adaptation and Convergent Evolution within the Jamesonia-Eriosorus Complex in High-Elevation Biodiverse Andean Hotspots

The recent uplift of the tropical Andes (since the late Pliocene or early Pleistocene) provided extensive ecological opportunity for evolutionary radiations. We test for phylogenetic and morphological evidence of adaptive radiation and convergent evolution to novel habitats (exposed, high-altitude páramo habitats) in the Andean fern genera Jamesonia and Eriosorus. We construct time-calibrated phylogenies for the Jamesonia-Eriosorus clade. We then use recent phylogenetic comparative methods to test for evolutionary transitions among habitats, associations between habitat and leaf morphology, and ecologically driven variation in the rate of morphological evolution. Páramo species (Jamesonia) display morphological adaptations consistent with convergent evolution in response to the demands of a highly exposed environment but these adaptations are associated with microhabitat use rather than the páramo per se. Species that are associated with exposed microhabitats (including Jamesonia and Eriorsorus) are characterized by many but short pinnae per frond whereas species occupying sheltered microhabitats (primarily Eriosorus) have few but long pinnae per frond. Pinnae length declines more rapidly with altitude in sheltered species. Rates of speciation are significantly higher among páramo than non-páramo lineages supporting the hypothesis of adaptation and divergence in the unique Páramo biodiversity hotspot

Endocrine regulation of predator-induced phenotypic plasticity

Elucidating the developmental and genetic control of phenotypic plasticity remains a central agenda in evolutionary ecology. Here, we investigate the physiological regulation of phenotypic plasticity induced by another organism, specifically predator-induced phenotypic plasticity in the model ecological and evolutionary organism Daphnia pulex. Our research centres on using molecular tools to test among alternative mechanisms of developmental control tied to hormone titres, receptors and their timing in the life cycle. First, we synthesize detail about predator-induced defenses and the physiological regulation of arthropod somatic growth and morphology, leading to a clear prediction that morphological defences are regulated by juvenile hormone and life-history plasticity by ecdysone and juvenile hormone. We then show how a small network of genes can differentiate phenotype expression between the two primary developmental control pathways in arthropods: juvenoid and ecdysteroid hormone signalling. Then, by applying an experimental gradient of predation risk, we show dose-dependent gene expression linking predator-induced plasticity to the juvenoid hormone pathway. Our data support three conclusions: (1) the juvenoid signalling pathway regulates predator-induced phenotypic plasticity; (2) the hormone titre (ligand), rather than receptor, regulates predator-induced developmental plasticity; (3) evolution has favoured the harnessing of a major, highly conserved endocrine pathway in arthropod development to regulate the response to cues about changing environments (risk) from another organism (predator)

Erythropoietin: A potent inducer of peripheral immuno/inflammatory modulation in autoimmune EAE

Background: Beneficial effects of short-term erythropoietin (EPO) theraphy have been demonstrated in several animal models of acute neurologic injury, including experimental autoimmune encephalomyelitis(EAE)-the animal model of multiple sclerosis. We have found that EPO treatment substantially reduces the acute clinical paralysis seen EAE mice and this improvements is accompanied by a large reduction in the mononuclear cell infiltration and downregulation of glial MHC class II expression within the inflamed CNS. Other reports have recently indicated that peripherally generated anti-inflammatory CD4 +Foxp3 3 regulatory T cells (Tregs) and the IL17-producing CD4+ T helper cell (Th17) subpopulations play key antagonistic roles in EAE pathogenesis. However, no information regardind the effects of EPO theraphy on the behavior of the general mononuclear-lymphocyte population, Tregs or Th17 cells in EAE has emerged. Methods and Findings: We first determined in vivo that EPO theraphy markedly suppressed MOG specific T cell proliferation and sharply reduced the number of reactive dendritic cells (CD11c positive) in EAE lumph modes during both inductive and later symptomatic phases of MOG 35-55 induced EAE. We then determined the effect in vivo of EPO on numbers of peripheral Treg cells and Th17 cells. We found that EPO treatment modulated immune balance in both the periphery and the inflamed spinal cord by promoting a large expansion in Treg cells, inhibiting Th17 polarization and abrogating proliferation of the antigen presenting dendritic cell population. Finally we utilized tissue culture assays to show that exposure to EPO in vitro similarly downregulated MOG-specific T cell proliferation and also greatly suppressed T cell production of pro-inflammatory cytokines. Conclusions: Taken together, our findings reveal an important new locus whereby EPO induces substantial long-term tissue protection in the host through signalling to several critical subsets of immune cells that reside in the peripheral lymphatic system.published_or_final_versio

Inversion of the balance between hydrophobic and hydrogen bonding interactions in protein folding and aggregation.

Identifying the forces that drive proteins to misfold and aggregate, rather than to fold into their functional states, is fundamental to our understanding of living systems and to our ability to combat protein deposition disorders such as Alzheimer's disease and the spongiform encephalopathies. We report here the finding that the balance between hydrophobic and hydrogen bonding interactions is different for proteins in the processes of folding to their native states and misfolding to the alternative amyloid structures. We find that the minima of the protein free energy landscape for folding and misfolding tend to be respectively dominated by hydrophobic and by hydrogen bonding interactions. These results characterise the nature of the interactions that determine the competition between folding and misfolding of proteins by revealing that the stability of native proteins is primarily determined by hydrophobic interactions between side-chains, while the stability of amyloid fibrils depends more on backbone intermolecular hydrogen bonding interactions

A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)

Meeting abstrac

Development of Continuous Flow Systems to Access Secondary Amines Through Previously Incompatible Biocatalytic Cascades**

A key aim of biocatalysis is to mimic the ability of eukaryotic cells to carry out multistep cascades in a controlled and selective way. As biocatalytic cascades get more complex, reactions become unattainable under typical batch conditions. Here a number of continuous flow systems were used to overcome batch incompatibility, thus allowing for successful biocatalytic cascades. As proof-of-principle, reactive carbonyl intermediates were generated in situ using alcohol oxidases, then passed directly to a series of packed-bed modules containing different aminating biocatalysts which accordingly produced a range of structurally distinct amines. The method was expanded to employ a batch incompatible sequential amination cascade via an oxidase/transaminase/imine reductase sequence, introducing different amine reagents at each step without cross-reactivity. The combined approaches allowed for the biocatalytic synthesis of the natural product 4O-methylnorbelladine

The effects of positive affect and episodic future thinking on temporal discounting, and healthy food demand and choice among overweight and obese individuals: Protocol for a pilot 2x2 factorial randomized controlled study

Background: Unhealthy behaviors (eg, poor food choices) contribute to obesity and numerous negative health outcomes, including multiple types of cancer and cardiovascular and metabolic diseases. To promote healthy food choice, diet interventions should build on the dual-system model to target the regulation and reward mechanisms that guide eating behavior. Episodic future thinking (EFT) has been shown to strengthen regulation mechanisms by reducing unhealthy food choice and temporal discounting (TD), a process of placing greater value on smaller immediate rewards over larger future rewards. However, these interventions do not target the reward mechanisms that could support healthy eating and strengthen the impact of EFT-anchored programs. Increasing positive affect (PosA) related to healthy food choices may target reward mechanisms by enhancing the rewarding effects of healthy eating. An intervention that increases self-regulation regarding unhealthy foods and the reward value of healthy foods will likely have a greater impact on eating behavior compared with interventions focused on either process alone. Objective: This study aimed to introduce a protocol that tests the independent and interactive effects of EFT and PosA on TD, food choice, and food demand in overweight and obese adults. Methods: This protocol describes a factorial, randomized, controlled pilot study that employs a 2 (affective imagery: positive, neutral) by 2 (EFT: yes, no) design in which participants are randomized to 1 of 4 guided imagery intervention arms. In total, 156 eligible participants will complete 2 lab visits separated by 5 days. At visit 1, participants complete surveys; listen to the audio guided imagery intervention; and complete TD, food demand, and food choice tasks. At visit 2, participants complete TD, food demand, and food choice tasks and surveys. Participants complete a daily food frequency questionnaire between visits 1 and 2. Analyses will compare primary outcome measures at baseline, post intervention, and at follow-up across treatment arms. Results: Funding notification was received on April 27, 2017, and the protocol was approved by the institutional review board on October 6, 2017. Feasibility testing of the protocol was conducted from February 21, 2018, to April 18, 2018, among the first 32 participants. As no major protocol changes were required at the end of the feasibility phase, these 32 participants were included in the target sample of 156 participants. Recruitment, therefore, continued immediately after the feasibility phase. When this manuscript was submitted, 84 participants had completed the protocol. Conclusions: Our research goal is to develop novel, theory-based interventions to promote and improve healthy decision-making and behaviors. The findings will advance decision-making research and have the potential to generate new neuroscience and psychological research to further understand these mechanisms and their interactions. Trial Registration: ISRCTN Registry ISRCTN11704675; http://www.isrctn.com/ISRCTN11704675 (Archived by WebCite at http://www.webcitation.org/760ouOoKG) International Registered Report Identifier (IRRID): DERR1-10.2196/1226

New insights from a structural economic dynamic approach to balance of payments constrained growth

In this paper it is shown that once-for-all variations in the level of the exchange rate may play an important role in the sectoral composition of the economy and this fact has important implications in terms of a disaggregated version of the Thirlwall’s law even if the argument of the quantitative unimportance of relative price movements holds. The growth rate of a country is then shown to be affected by once-for-all movements in the level of nominal exchange rates and the concept of a natural exchange rate is introduced