Pathways for the Photoreduction of Fumarate on ZnS

Semiconductor mineral particles can act as photocatalysts for organic redox reactions that occur enzymatically in modern biological metabolic pathways. Semiconductor mineral-mediated photocatalysis may have contributed to the prebiotic synthesis of organic acids on the early Earth, but assessing the plausibility of this hypothesis is impeded by the lack of knowledge about the mechanisms for light-driven organic redox reactions on mineral surfaces. We selected one step in the reverse tricarboxylic acid (rTCA) cycle, the reduction of fumarate to succinate, that has been shown to be photocatalyzed by zinc sulfide (ZnS). Using static and time-resolved optical emission and absorption spectroscopy, we studied the adsorption of fumarate and the rates and pathways for charge transfer. We find that ZnS transfers photoexcited electrons to bound and dissolved fumarate on a wide range of time scales but not to succinate, supporting the concept that ZnS mediated photoreduction of fumarate could have operated in oceans of the early Earth. Optical transient absorption (TA) spectroscopy identified a signature tentatively attributed to the fumarate radical anion that is stable for at least 8 ns, providing evidence that fumarate photoreduction under solar illumination levels occurs by successive photoelectron transfer. The model for electronic excitation, relaxation, and interfacial charge-transfer processes in ZnS provided here will inform all future studies of the photochemical reactions of this mineral

The SMFA program for quantum chemistry calculations on large molecules

SMFA is a general program package for performing quantum chemistry calculations on large molecules, using an energy-based fragmentation approach. The program can calculate electronic energies, energy gradients and second derivatives; perform geometry optimization; find first order saddle points (transition states); perform energy optimized scans along a user-defined path; and evaluate various molecular properties. The program can use any of the following quantum chemistry packages: GAMESS(US), GAUSSIAN, NWChem and Q-Chem. In addition, SMFA provides a number of utility programs that, inter alia, calculate vibrational frequencies and infrared spectra with isotopic substitutions, the electrostatic potential on the solvent-accessible-surface, and isodesmic and higher order near-iso-energetic reaction schemes. Calculations of the electronic energy and related properties can be carried out using a scheme that provides a computation time that is linearly dependent on the size of the molecule or, if the user has enough processing units available, in a walltime that is independent of the size of the molecule

The factor structure of the Forms of Self-Criticising/Attacking & Self-Reassuring Scale in thirteen distinct populations

There is considerable evidence that self-criticism plays a major role in the vulnerability to and recovery from psychopathology. Methods to measure this process, and its change over time, are therefore important for research in psychopathology and well-being. This study examined the factor structure of a widely used measure, the Forms of Self-Criticising/Attacking & Self-Reassuring Scale in thirteen nonclinical samples (N = 7510) from twelve different countries: Australia (N = 319), Canada (N = 383), Switzerland (N = 230), Israel (N = 476), Italy (N = 389), Japan (N = 264), the Netherlands (N = 360), Portugal (N = 764), Slovakia (N = 1326), Taiwan (N = 417), the United Kingdom 1 (N = 1570), the United Kingdom 2 (N = 883), and USA (N = 331). This study used more advanced analyses than prior reports: a bifactor item-response theory model, a two-tier item-response theory model, and a non-parametric item-response theory (Mokken) scale analysis. Although the original three-factor solution for the FSCRS (distinguishing between Inadequate-Self, Hated-Self, and Reassured-Self) had an acceptable fit, two-tier models, with two general factors (Self-criticism and Self-reassurance) demonstrated the best fit across all samples. This study provides preliminary evidence suggesting that this two-factor structure can be used in a range of nonclinical contexts across countries and cultures. Inadequate-Self and Hated-Self might not by distinct factors in nonclinical samples. Future work may benefit from distinguishing between self-correction versus shame-based self-criticism.Peer reviewe

Clustering and the hyperbolic geometry of complex networks

Clustering is a fundamental property of complex networks and it is the mathematical expression of a ubiquitous phenomenon that arises in various types of self-organized networks such as biological networks, computer networks or social networks. In this paper, we consider what is called the global clustering coefficient of random graphs on the hyperbolic plane. This model of random graphs was proposed recently by Krioukov et al. as a mathematical model of complex networks, under the fundamental assumption that hyperbolic geometry underlies the structure of these networks. We give a rigorous analysis of clustering and characterize the global clustering coefficient in terms of the parameters of the model. We show how the global clustering coefficient can be tuned by these parameters and we give an explicit formula for this function.Comment: 51 pages, 1 figur

Axion Protection from Flavor

The QCD axion fails to solve the strong CP problem unless all explicit PQ violating, Planck-suppressed, dimension n<10 operators are forbidden or have exponentially small coefficients. We show that all theories with a QCD axion contain an irreducible source of explicit PQ violation which is proportional to the determinant of the Yukawa interaction matrix of colored fermions. Generically, this contribution is of low operator dimension and will drastically destabilize the axion potential, so its suppression is a necessary condition for solving the strong CP problem. We propose a mechanism whereby the PQ symmetry is kept exact up to n=12 with the help of the very same flavor symmetries which generate the hierarchical quark masses and mixings of the SM. This "axion flavor protection" is straightforwardly realized in theories which employ radiative fermion mass generation and grand unification. A universal feature of this construction is that the heavy quark Yukawa couplings are generated at the PQ breaking scale.Comment: 16 pages, 2 figure

Boundaries of Disk-like Self-affine Tiles

Let $T:= T(A, {\mathcal D})$ be a disk-like self-affine tile generated by an integral expanding matrix $A$ and a consecutive collinear digit set ${\mathcal D}$, and let $f(x)=x^{2}+px+q$ be the characteristic polynomial of $A$. In the paper, we identify the boundary $\partial T$ with a sofic system by constructing a neighbor graph and derive equivalent conditions for the pair $(A,{\mathcal D})$ to be a number system. Moreover, by using the graph-directed construction and a device of pseudo-norm $\omega$, we find the generalized Hausdorff dimension $\dim_H^{\omega} (\partial T)=2\log \rho(M)/\log |q|$ where $\rho(M)$ is the spectral radius of certain contact matrix $M$. Especially, when $A$ is a similarity, we obtain the standard Hausdorff dimension $\dim_H (\partial T)=2\log \rho/\log |q|$ where $\rho$ is the largest positive zero of the cubic polynomial $x^{3}-(|p|-1)x^{2}-(|q|-|p|)x-|q|$, which is simpler than the known result.Comment: 26 pages, 11 figure

Phylogenetic Codivergence Supports Coevolution of Mimetic Heliconius Butterflies

The unpalatable and warning-patterned butterflies _Heliconius erato_ and _Heliconius melpomene_ provide the best studied example of mutualistic M&#xfc;llerian mimicry, thought &#x2013; but rarely demonstrated &#x2013; to promote coevolution. Some of the strongest available evidence for coevolution comes from phylogenetic codivergence, the parallel divergence of ecologically associated lineages. Early evolutionary reconstructions suggested codivergence between mimetic populations of _H. erato_ and _H. melpomene_, and this was initially hailed as the most striking known case of coevolution. However, subsequent molecular phylogenetic analyses found discrepancies in phylogenetic branching patterns and timing (topological and temporal incongruence) that argued against codivergence. We present the first explicit cophylogenetic test of codivergence between mimetic populations of _H. erato_ and _H. melpomene_, and re-examine the timing of these radiations. We find statistically significant topological congruence between multilocus coalescent population phylogenies of _H. erato_ and _H. melpomene_, supporting repeated codivergence of mimetic populations. Divergence time estimates, based on a Bayesian coalescent model, suggest that the evolutionary radiations of _H. erato_ and _H. melpomene_ occurred over the same time period, and are compatible with a series of temporally congruent codivergence events. This evidence supports a history of reciprocal coevolution between M&#xfc;llerian co-mimics characterised by phylogenetic codivergence and parallel phenotypic change

Satellite remote sensing data can be used to model marine microbial metabolite turnover

Sampling ecosystems, even at a local scale, at the temporal and spatial resolution necessary to capture natural variability in microbial communities are prohibitively expensive. We extrapolated marine surface microbial community structure and metabolic potential from 72 16S rRNA amplicon and 8 metagenomic observations using remotely sensed environmental parameters to create a system-scale model of marine microbial metabolism for 5904 grid cells (49 km2) in the Western English Chanel, across 3 years of weekly averages. Thirteen environmental variables predicted the relative abundance of 24 bacterial Orders and 1715 unique enzyme-encoding genes that encode turnover of 2893 metabolites. The genes’ predicted relative abundance was highly correlated (Pearson Correlation 0.72, P-value <10−6) with their observed relative abundance in sequenced metagenomes. Predictions of the relative turnover (synthesis or consumption) of CO2 were significantly correlated with observed surface CO2 fugacity. The spatial and temporal variation in the predicted relative abundances of genes coding for cyanase, carbon monoxide and malate dehydrogenase were investigated along with the predicted inter-annual variation in relative consumption or production of ~3000 metabolites forming six significant temporal clusters. These spatiotemporal distributions could possibly be explained by the co-occurrence of anaerobic and aerobic metabolisms associated with localized plankton blooms or sediment resuspension, which facilitate the presence of anaerobic micro-niches. This predictive model provides a general framework for focusing future sampling and experimental design to relate biogeochemical turnover to microbial ecology

Computational modelling of cancerous mutations in the EGFR/ERK signalling pathway

This article has been made available through the Brunel Open Access Publishing Fund - Copyright @ 2009 Orton et al.BACKGROUND: The Epidermal Growth Factor Receptor (EGFR) activated Extracellular-signal Regulated Kinase (ERK) pathway is a critical cell signalling pathway that relays the signal for a cell to proliferate from the plasma membrane to the nucleus. Deregulation of the EGFR/ERK pathway due to alterations affecting the expression or function of a number of pathway components has long been associated with numerous forms of cancer. Under normal conditions, Epidermal Growth Factor (EGF) stimulates a rapid but transient activation of ERK as the signal is rapidly shutdown. Whereas, under cancerous mutation conditions the ERK signal cannot be shutdown and is sustained resulting in the constitutive activation of ERK and continual cell proliferation. In this study, we have used computational modelling techniques to investigate what effects various cancerous alterations have on the signalling flow through the ERK pathway. RESULTS: We have generated a new model of the EGFR activated ERK pathway, which was verified by our own experimental data. We then altered our model to represent various cancerous situations such as Ras, B-Raf and EGFR mutations, as well as EGFR overexpression. Analysis of the models showed that different cancerous situations resulted in different signalling patterns through the ERK pathway, especially when compared to the normal EGF signal pattern. Our model predicts that cancerous EGFR mutation and overexpression signals almost exclusively via the Rap1 pathway, predicting that this pathway is the best target for drugs. Furthermore, our model also highlights the importance of receptor degradation in normal and cancerous EGFR signalling, and suggests that receptor degradation is a key difference between the signalling from the EGF and Nerve Growth Factor (NGF) receptors. CONCLUSION: Our results suggest that different routes to ERK activation are being utilised in different cancerous situations which therefore has interesting implications for drug selection strategies. We also conducted a comparison of the critical differences between signalling from different growth factor receptors (namely EGFR, mutated EGFR, NGF, and Insulin) with our results suggesting the difference between the systems are large scale and can be attributed to the presence/absence of entire pathways rather than subtle difference in individual rate constants between the systems.This work was funded by the Department of Trade and Industry (DTI), under their Bioscience Beacon project programme. AG was funded by an industrial PhD studentship from Scottish Enterprise and Cyclacel

Evaluation of Daily Low-Dose Prednisolone During Upper Respiratory Tract Infection to Prevent Relapse in Children With Relapsing Steroid-Sensitive Nephrotic Syndrome: The PREDNOS 2 Randomized Clinical Trial

Importance: In children with corticosteroid-sensitive nephrotic syndrome, many relapses are triggered by upper respiratory tract infections. Four small studies found that administration of daily low-dose prednisolone for 5 to 7 days at the time of an upper respiratory tract infection reduced the risk of relapse, but the generalizability of their findings is limited by location of the studies and selection of study population. / Objective: To investigate the use of daily low-dose prednisolone for the treatment of upper respiratory tract infection-related relapses. / Design, Setting, and Participants: This double-blind, placebo-controlled randomized clinical trial (Prednisolone in Nephrotic Syndrome [PREDNOS] 2) evaluated 365 children with relapsing steroid-sensitive nephrotic syndrome with and without background immunosuppressive treatment at 122 pediatric departments in the UK from February 1, 2013, to January 31, 2020. Data from the modified intention-to-treat population were analyzed from July 1, 2020, to December 31, 2020. / Interventions: At the start of an upper respiratory tract infection, children received 6 days of prednisolone, 15 mg/m2 daily, or matching placebo preparation. Those already taking alternate-day prednisolone rounded their daily dose using trial medication to the equivalent of 15 mg/m2 daily or their alternate-day dose, whichever was greater. / Main Outcomes and Measures: The primary outcome was the incidence of first upper respiratory tract infection-related relapse. Secondary outcomes included overall rate of relapse, changes in background immunosuppressive treatment, cumulative dose of prednisolone, rates of serious adverse events, incidence of corticosteroid adverse effects, and quality of life. / Results: The modified intention-to-treat analysis population comprised 271 children (mean [SD] age, 7.6 [3.5] years; 174 [64.2%] male), with 134 in the prednisolone arm and 137 in the placebo arm. The number of patients experiencing an upper respiratory tract infection-related relapse was 56 of 131 (42.7%) in the prednisolone arm and 58 of 131 (44.3%) in the placebo arm (adjusted risk difference, -0.02; 95% CI, -0.14 to 0.10; P = .70). No evidence was found that the treatment effect differed according to background immunosuppressive treatment. No significant differences were found in secondary outcomes between the treatment arms. A post hoc subgroup analysis assessing the primary outcome in 54 children of South Asian ethnicity (risk ratio, 0.66; 95% CI, 0.40-1.10) vs 208 children of other ethnicity (risk ratio, 1.11; 95% CI, 0.81-1.54) found no difference in efficacy of intervention in those of South Asian ethnicity (test for interaction P = .09). / Conclusions and Relevance: The results of PREDNOS 2 suggest that administering 6 days of daily low-dose prednisolone at the time of an upper respiratory tract infection does not reduce the risk of relapse of nephrotic syndrome in children in the UK. Further work is needed to investigate interethnic differences in treatment response. / Trial Registration: isrctn.org / Identifier: ISRCTN10900733; EudraCT 2012-003476-39