Neutrinoless double beta decay in four-neutrino models

The most stringent constraint on the so-called effective electron neutrino mass from the present neutrinoless double beta decay experiments is |M_{ee}| < 0.2 eV, while the planned next generation experiment GENIUS is anticipated to reach a considerably more stringent limit |M_{ee}|< 0.001 eV. We investigate the constraints these bounds set on the neutrino masses and mixings of neutrinos in four-neutrino models where there exists a sterile neutrino along with the three ordinary neutrinos. We find that the GENIUS experiment would be sensitive to the electron neutrino masses down to the limit m_{\nu_e}\lsim 0.024 eV in such a scenario.Comment: 15 pages, 1 figur

Living through unsuccessful conception attempts: : a grounded theory of resilience among women undergoing fertility treatment

This is an Accepted Manuscript of an article published by Taylor & Francis in Journal of Reproductive and Infant Psychology on 6 May 2017, available online: https://doi.org/10.1080/02646838.2017.1320366.Objective: To provide a model of resilience among women undergoing fertility treatments, who experience repeated unsuccessful conception attempts. Background: Assisted reproductive treatment is emotionally and physically challenging. Women undergoing such treatments report experiencing high levels of anxiety and depression. There continues to be a lack of understanding of the process women go through to adapt to the challenges associated with fertility treatment, in order to continue to pursue their goal of pregnancy. Method: The study employed a qualitative Grounded Theory design. Eleven women aged between 24 and 42 years took part in individual semi-structured interviews around their experiences of living through unsuccessful fertility treatment attempts. Results: Three core categories were identified: ‘Appraisal’; ‘Stepping away from treatment’; and ‘Building self up for the next attempt’. Following the failure of treatment, participants appraised their ability to carry on with further treatment attempts. Those who felt they had depleted their resources through the cycle of attempting pregnancy had taken a step back from the treatment cycle to reconnect with themselves and gather sufficient resources to attempt treatment again. During preparation for the next treatment, participants demonstrated their resilience by taking steps to build up their resources, such as nurturing their strength and taking control of their fertility experience. Conclusions: Women undergoing fertility treatment demonstrate their resilience through a variety of actions that enable them to continue to pursue their pregnancy goal. Clinical staff should be mindful of their clients’ need to withdraw from the treatment cycle and offer support to enable them to do this.Peer reviewe

Structural diversity in the AdoMet radical enzyme superfamily

AdoMet radical enzymes are involved in processes such as cofactor biosynthesis, anaerobic metabolism, and natural product biosynthesis. These enzymes utilize the reductive cleavage of S-adenosylmethionine (AdoMet) to afford l-methionine and a transient 5′-deoxyadenosyl radical, which subsequently generates a substrate radical species. By harnessing radical reactivity, the AdoMet radical enzyme superfamily is responsible for an incredible diversity of chemical transformations. Structural analysis reveals that family members adopt a full or partial Triose-phosphate Isomerase Mutase (TIM) barrel protein fold, containing core motifs responsible for binding a catalytic [4Fe–4S] cluster and AdoMet. Here we evaluate over twenty structures of AdoMet radical enzymes and classify them into two categories: ‘traditional’ and ‘ThiC-like’ (named for the structure of 4-amino-5-hydroxymethyl-2-methylpyrimidine phosphate synthase (ThiC)). In light of new structural data, we reexamine the ‘traditional’ structural motifs responsible for binding the [4Fe–4S] cluster and AdoMet, and compare and contrast these motifs with the ThiC case. We also review how structural data combine with biochemical, spectroscopic, and computational data to help us understand key features of this enzyme superfamily, such as the energetics, the triggering, and the molecular mechanisms of AdoMet reductive cleavage. This article is part of a Special Issue entitled: Radical SAM Enzymes and Radical Enzymology.Wellcome Trust (London, England) (091162/Z/10/Z)National Science Foundation (U.S.) (NSF Grant MCB-0543833)Howard Hughes Medical Institute (Investigator

Revealing solvent-dependent folding behaviour of mycolic acids from Mycobacterium tuberculosis by advanced simulation analysis

Mycobacterium tuberculosis remains a persistent pathogen, partly due to its lipid rich cell wall, of which mycolic acids (MAs) are a major component. The fluidity and conformational flexibilities of different MAs in the bacterial cell wall significantly influence its properties, function, and observed pathogenicity; thus, a proper conformational description of different MAs in different environments (e.g., in vacuum, in solution, in monolayers) can inform about their potential role in the complex setup of the bacterial cell wall. Previously, we have shown that molecular dynamics (MD) simulations of MA folding in vacuo can be used to characterize MA conformers in seven groupings relating to bending at the functional groups (W, U and Z-conformations). Providing a new OPLS-based forcefield parameterization for the critical cyclopropyl group of MAs and extensive simulations in explicit solvents (TIP4P water, hexane), we now present a more complete picture of MA folding properties together with improved simulation analysis techniques. We show that the ‘WUZ’ distance-based analysis can be used to pinpoint conformers with hairpin bends at the functional groups, with these conformers constituting only a fraction of accessible conformations. Applying principle component analysis (PCA) and refinement using free energy landscapes (FELs), we are able to discriminate a complete and unique set of conformational preferences for representative alpha-, methoxy- and keto-MAs, with overall preference for folded conformations. A control backbone-MA without any mero-chain functional groups showed significantly less folding in the mero-chain, confirming the role of functionalization in directing folding. Keto-MA showed the highest percentage of WUZ-type conformations and, in particular, a tendency to fold at its alpha-methyl trans-cyclopropane group, in agreement with results from Villeneuve et al. MAs demonstrate similar folding in vacuum and water, with a majority of folded conformations around the W-conformation, although the molecules are more flexible in vacuum than in water. Exchange between conformations, with a disperse distribution that includes unfolded conformers, is common in hexane for all MAs, although with more organization for Keto-MA. Globular, folded conformations are newly defined and may be specifically relevant in biofilms

Proteins in Ionic Liquids: Reactions, Applications and Futures

Biopolymer processing and handling is greatly facilitated by the use of ionic liquids, given the increased solubility, and in somecases, structural stability imparted to these molecules. Focussing on proteins, we highlight here not just the key drivers behind protein-ionic liquid interactions that facilitate these functionalities, but address relevant current and potential applications of protein-ionic liquid interactions, including areas of future interest

If It Is Hard, It Is Worth Doing: Engineering Radical Enzymes from Anaerobes

With a pressing need for sustainable chemistries, radical enzymes from anaerobes offer a shortcut for many chemical transformations and deliver highly sought-after functionalizations such as late-stage C-H functionalization, C-C bond formation, and carbon-skeleton rearrangements, among others. The challenges in handling these oxygen-sensitive enzymes are reflected in their limited industrial exploitation, despite what they may deliver. With an influx of structures and mechanistic understanding, the scope for designed radical enzymes to deliver wanted processes becomes ever closer. Combined with new advances in computational methods and workflows for these complex systems, the outlook for an increased use of radical enzymes in future processes is exciting

Differential spontaneous folding of mycolic acids from Mycobacterium tuberculosis

AbstractMycolic acids are structural components of the mycobacterial cell wall that have been implicated in the pathogenicity and drug resistance of certain mycobacterial species. They also offer potential in areas such as rapid serodiagnosis of human and animal tuberculosis. It is increasingly recognized that conformational behavior of mycolic acids is very important in understanding all aspects of their function. Atomistic molecular dynamics simulations, in vacuo, of stereochemically defined Mycobacterium tuberculosis mycolic acids show that they fold spontaneously into reproducible conformational groupings. One of the three characteristic mycolate types, the keto-mycolic acids, behaves very differently from either α-mycolic acids or methoxy-mycolic acids, suggesting a distinct biological role. However, subtle conformational behavioral differences between all the three mycolic acid types indicate that cooperative interplay of individual mycolic acids may be important in the biophysical properties of the mycobacterial cell envelope and therefore in pathogenicity

Activation of Glycyl Radical Enzymes─Multiscale Modeling Insights into Catalysis and Radical Control in a Pyruvate Formate-Lyase-Activating Enzyme

Pyruvate formate-lyase (PFL) is a glycyl radical enzyme (GRE) playing a pivotal role in the metabolism of strict and facultative anaerobes. Its activation is carried out by a PFL-activating enzyme, a member of the radical S-adenosylmethionine (rSAM) superfamily of metalloenzymes, which introduces a glycyl radical into the Gly radical domain of PFL. The activation mechanism is still not fully understood and is structurally based on a complex with a short model peptide of PFL. Here, we present extensive molecular dynamics simulations in combination with quantum mechanics/molecular mechanics (QM/MM)-based kinetic and thermodynamic reaction evaluations of a more complete activation model comprising the 49 amino acid long C-terminus region of PFL. We reveal the benefits and pitfalls of the current activation model, providing evidence that the bound peptide conformation does not resemble the bound protein-protein complex conformation with PFL, with implications for the activation process. Substitution of the central glycine with (S)- and (R)-alanine showed excellent binding of (R)-alanine over unstable binding of (S)-alanine. Radical stabilization calculations indicate that a higher radical stability of the glycyl radical might not be the sole origin of the evolutionary development of GREs. QM/MM-derived radical formation kinetics further demonstrate feasible activation barriers for both peptide and C-terminus activation, demonstrating why the crystalized model peptide system is an excellent inhibitory system for natural activation. This new evidence supports the theory that GREs converged on glycyl radical formation due to the better conformational accessibility of the glycine radical loop, rather than the highest radical stability of the formed peptide radicals

Perspective — Redox Ionic Liquid Electrolytes for Supercapattery

Adding redox activity into ionic liquids (ILs) extends their practical roles beyond an inert ionic conductor or electrolyte for applications in electrochemical energy storage. Especially for supercapatteries, redox ILs are desirable because they can contribute to increasing the charge storage capacity by merging the capacitive and Nernstian storage mechanisms without compromising their intrinsic wide potential windows. Several prospects of redox ILs are identified and discussed for optimising performance in supercapatteries