Fluorinated models of the iron-only hydrogenase: An electrochemical study of the influence of an electron-withdrawing bridge on the proton reduction overpotential and catalyst stability

AbstractHere we report the synthesis, electrochemistry and electrocatalytic activity of Fe2(CO)6(μ-SC6F5)2 (1) where the highly fluorinated bridge is electron-withdrawing, resulting in decreased electron-density at the iron–iron bond. Additionally we discuss the related substituted complexes Fe2(CO)5(PPh3)(μ-SC6F5)2 (2) and Fe2(CO)4(μ-Ph2PCH2PPh2)(μ-SC6F5)2 (3). As none of the complexes could be protonated in their neutral form it was found that proton reduction catalysis in the presence of strong acid (HBF4) took place at the potential of the first reduction of complex 1 and 3, following an EC mechanism. Complex 2 was unstable in the presence of strong acid. For 1 the potential at which proton reduction took place represented a relatively mild reduction potential (−1.15V vs. Fc/Fc+ in acetonitrile) that was comparable to examples of similar complexes in the literature. Complex 1 generated a small concentration of a highly catalytic species after electrochemical reduction, which we attribute to cleavage of the Fe–Fe bond and formation of a mono-nuclear iron species or to Fe–S bond breakage generating a vacant coordination site. The contributions to the catalytic currents were simulated using DigiSim, where it was found that the rate limiting step for 3 was the elimination of H2. It was also found that the highly catalytic species generated after reduction of 1 was more basic than 1− and also that protonation of this species was faster

A novel angiotensin I-converting enzyme mutation (S333W) impairs N-domain enzymatic cleavage of the anti-fibrotic peptide, AcSDKP

BACKGROUND: Angiotensin I-converting enzyme (ACE) has two functional N- and C-domain active centers that display differences in the metabolism of biologically-active peptides including the hemoregulatory tetrapeptide, Ac-SDKP, hydrolysed preferentially by the N domain active center. Elevated Ac-SDKP concentrations are associated with reduced tissue fibrosis. RESULTS: We identified a patient of African descent exhibiting unusual blood ACE kinetics with reduced relative hydrolysis of two synthetic ACE substrates (ZPHL/HHL ratio) suggestive of the ACE N domain center inactivation. Inhibition of blood ACE activity by anti-catalytic mAbs and ACE inhibitors and conformational fingerprint of blood ACE suggested overall conformational changes in the ACE molecule and sequencing identified Ser333Trp substitution in the N domain of ACE. In silico analysis demonstrated S333W localized in the S 1 pocket of the active site of the N domain with the bulky Trp adversely affecting binding of ACE substrates due to steric hindrance. Expression of mutant ACE (S333W) in CHO cells confirmed altered kinetic properties of mutant ACE and conformational changes in the N domain. Further, the S333W mutant displayed decreased ability (5-fold) to cleave the physiological substrate AcSDKP compared to wild-type ACE. Conclusions and Significance A novel Ser333Trp ACE mutation results in dramatic changes in ACE kinetic properties and lowered clearance of Ac-SDKP. Individuals with this mutation (likely with significantly increased levels of the hemoregulatory tetrapeptide in blood and tissues), may confer protection against fibrosis

Evidence for Habitual and Goal-Directed Behavior Following Devaluation of Cocaine: A Multifaceted Interpretation of Relapse

BACKGROUND:Cocaine addiction is characterized as a chronically relapsing disorder. It is believed that cues present during self-administration become learned and increase the probability that relapse will occur when they are confronted during abstinence. However, the way in which relapse-inducing cues are interpreted by the user has remained elusive. Recent theories of addiction posit that relapse-inducing cues cause relapse habitually or automatically, bypassing processing information related to the consequences of relapse. Alternatively, other theories hypothesize that relapse-inducing cues produce an expectation of the drug's consequences, designated as goal-directed relapse. Discrete discriminative stimuli signaling the availability of cocaine produce robust cue-induced responding after thirty days of abstinence. However, it is not known whether cue-induced responding is a goal-directed action or habit. METHODOLOGY/PRINCIPAL FINDINGS:We tested whether cue-induced responding is a goal-directed action or habit by explicitly pairing or unpairing cocaine with LiCl-induced sickness (n = 7/group), thereby decreasing or not altering the value of cocaine, respectively. Following thirty days of abstinence, no difference in responding between groups was found when animals were reintroduced to the self-administration environment alone, indicating habitual behavior. However, upon discriminative stimulus presentations, cocaine-sickness paired animals exhibited decreased cue-induced responding relative to unpaired controls, indicating goal-directed behavior. In spite of the difference between groups revealed during abstinent testing, no differences were found between groups when animals were under the influence of cocaine. CONCLUSIONS/SIGNIFICANCE:Unexpectedly, both habitual and goal-directed responding occurred during abstinent testing. Furthermore, habitual or goal-directed responding may have been induced by cues that differed in their correlation with the cocaine infusion. Non-discriminative stimulus cues were weak correlates of the infusion, which failed to evoke a representation of the value of cocaine and led to habitual behavior. However, the discriminative stimulus-nearly perfectly correlated with the infusion-likely evoked a representation of the value of the infusion and led to goal-directed behavior. These data indicate that abstinent cue-induced responding is multifaceted, dynamically engendering habitual or goal-directed behavior. Moreover, since goal-directed behavior terminated habitual behavior during testing, therapeutic approaches aimed at reducing the perceived value of cocaine in addicted individuals may reduce the capacity of cues to induce relapse

Transport time scales in soil erosion modelling

Unlike sediment transport in rivers, erosion of agricultural soil must overcome its cohesive strength to move soil particles into suspension. Soil particle size variability also leads to fall velocities covering many orders of magnitude, and hence to different suspended travel distances in overland flow. Consequently, there is a large range of inherent time scales involved in transport of eroded soil. For conditions where there is a constant rainfall rate and detachment is the dominant erosion mechanism, we use the Hairsine-Rose (HR) model to analyze these timescales, to determine their magnitude (bounds) and to provide simple approximations for them. We show that each particle size produces both fast and slow timescales. The fast timescale controls the rapid adjustment away from experimental initial conditions – this happens so quickly that it cannot be measured in practice. The slow time scales control the subsequent transition to steady state and are so large that true steady state is rarely achieved in laboratory experiments. Both the fastest and slowest time scales are governed by the largest particle size class. Physically, these correspond to the rate of vertical movement between suspension and the soil bed, and the time to achieve steady state, respectively. For typical distributions of size classes, we also find that there is often a single dominant time scale that governs the growth in the total mass of sediment in the non-cohesive deposited layer. This finding allows a considerable simplification of the HR model leading to analytical expressions for the evolution of suspended and deposited layer concentrations

Systems serology detects functionally distinct coronavirus antibody features in children and elderly

The hallmarks of COVID-19 are higher pathogenicity and mortality in the elderly compared to children. Examining baseline SARS-CoV-2 cross-reactive immunological responses, induced by circulating human coronaviruses (hCoVs), is needed to understand such divergent clinical outcomes. Here we show analysis of coronavirus antibody responses of pre-pandemic healthy children (n = 89), adults (n = 98), elderly (n = 57), and COVID-19 patients (n = 50) by systems serology. Moderate levels of cross-reactive, but non-neutralizing, SARS-CoV-2 antibodies are detected in pre-pandemic healthy individuals. SARS-CoV-2 antigen-specific Fcγ receptor binding accurately distinguishes COVID-19 patients from healthy individuals, suggesting that SARS-CoV-2 infection induces qualitative changes to antibody Fc, enhancing Fcγ receptor engagement. Higher cross-reactive SARS-CoV-2 IgA and IgG are observed in healthy elderly, while healthy children display elevated SARS-CoV-2 IgM, suggesting that children have fewer hCoV exposures, resulting in less-experienced but more polyreactive humoral immunity. Age-dependent analysis of COVID-19 patients, confirms elevated class-switched antibodies in elderly, while children have stronger Fc responses which we demonstrate are functionally different. These insights will inform COVID-19 vaccination strategies, improved serological diagnostics and therapeutics

Cognitive behaviour therapy plus aerobic exercise training to increase activity in patients with myotonic dystrophy type 1 (DM1) compared to usual care (OPTIMISTIC):Study protocol for randomised controlled trial

Peer reviewedPublisher PD

Storylines: an alternative approach to representing uncertainty in physical aspects of climate change

As climate change research becomes increasingly applied, the need for actionable information is growing rapidly. A key aspect of this requirement is the representation of uncertainties. The conventional approach to representing uncertainty in physical aspects of climate change is probabilistic, based on ensembles of climate model simulations. In the face of deep uncertainties, the known limitations of this approach are becoming increasingly apparent. An alternative is thus emerging which may be called a ‘storyline’ approach. We define a storyline as a physically self-consistent unfolding of past events, or of plausible future events or pathways. No a priori probability of the storyline is assessed; emphasis is placed instead on understanding the driving factors involved, and the plausibility of those factors. We introduce a typology of four reasons for using storylines to represent uncertainty in physical aspects of climate change: (i) improving risk awareness by framing risk in an event-oriented rather than a probabilistic manner, which corresponds more directly to how people perceive and respond to risk; (ii) strengthening decision-making by allowing one to work backward from a particular vulnerability or decision point, combining climate change information with other relevant factors to address compound risk and develop appropriate stress tests; (iii) providing a physical basis for partitioning uncertainty, thereby allowing the use of more credible regional models in a conditioned manner and (iv) exploring the boundaries of plausibility, thereby guarding against false precision and surprise. Storylines also offer a powerful way of linking physical with human aspects of climate change