Unlocking the full evolutionary potential of artificial metalloenzymes through direct metal-protein coordination: A review of recent advances for catalyst development

Generation of artificial metalloenzymes (ArMs) has gained much inspiration from the general understanding of natural metalloenzymes. Over the last decade, a multitude of methods generating transition metal-protein hybrids have been developed and many of these new-to-nature constructs catalyse reactions previously reserved for the realm of synthetic chemistry. This perspective will focus on ArMs incorporating 4d and 5d transition metals. It aims to summarise the significant advances made to date and asks whether there are chemical strategies, used in nature to optimise metal catalysts, that have yet to be fully recognised in the synthetic enzyme world, particularly whether artificial enzymes produced to date fully take advantage of the structural and energetic context provided by the protein. Further, the argument is put forward that, based on precedence, in the majority of naturally evolved metalloenzymes the direct coordination bonding between the metal and the protein scaffold is integral to catalysis. Therefore, the protein can attenuate metal activity by positioning ligand atoms in the form of amino acids, as well as making non-covalent contributions to catalysis, through intermolecular interactions that pre-organise substrates and stabilise transition states. This highlights the often neglected but crucial element of natural systems that is the energetic contribution towards activating metal centres through protein fold energy. Finally, general principles needed for a different approach to the formation of ArMs are set out, utilising direct coordination inspired by the activation of an organometallic cofactor upon protein binding. This methodology, observed in nature, delivers true interdependence between metal and protein. When combined with the ability to efficiently evolve enzymes, new problems in catalysis could be addressed in a faster and more specific manner than with simpler small molecule catalysts.</jats:p

'It felt like it was night all the time' : listening to the experiences of birth mothers whose children have been taken into care or adopted

The child care literature consistently reports a lack of support for birth mothers following their child being taken into care or adopted. This is despite consistent evidence of the long-term consequences of the removal of children on their mental health. The aim of this study is to explore the effects of separation, the subsequent sense of identity and the experience of contact and support throughout the process. Semi-structured interviews were conducted with seven mothers recruited from birth mother support groups and the transcripts analysed using Interpretative Phenomenological Analysis (IPA). Four themes emerged: ‘no one in my corner’; disconnecting from emotion; renegotiating identity; and the children are gone but still here. The findings contribute to our understanding of the experiences of birth mothers whose children are removed from their care and are discussed within a range of psychological theories.Peer reviewedFinal Accepted Versio

Constraints on energetic particles in the Fleischmann-Pons experiment

In recent Fleischmann–Pons experiments carried out by different groups, a thermal signal is seen indicative of excess energy production of a magnitude much greater than can be accounted for by chemistry. Correlated with the excess heat appears to be 4He, with the associated energy near 24 MeV per helium atom. In nuclear reactions, the energy produced is expressed through the kinetic energy of the products; hence, it would be natural to assume that some of the reaction energy ends up as kinetic energy of the 4He nucleus. Depending on the energy that the helium nucleus is born with, it will result in radiation (such as neutrons or x-rays) that can be seen outside of the cell. We have computed estimates of the expected neutron and x-ray emission as a function of helium energy and compared the results with upper limits taken from experiments. Experimental results with upper limits of neutron emission between 0.008 and 0.8 n/J are found to correspond to upper limits in alpha energy between 6.2 and 20.2 keV

Towards Omni-Tomography—Grand Fusion of Multiple Modalities for Simultaneous Interior Tomography

We recently elevated interior tomography from its origin in computed tomography (CT) to a general tomographic principle, and proved its validity for other tomographic modalities including SPECT, MRI, and others. Here we propose “omni-tomography”, a novel concept for the grand fusion of multiple tomographic modalities for simultaneous data acquisition in a region of interest (ROI). Omni-tomography can be instrumental when physiological processes under investigation are multi-dimensional, multi-scale, multi-temporal and multi-parametric. Both preclinical and clinical studies now depend on in vivo tomography, often requiring separate evaluations by different imaging modalities. Over the past decade, two approaches have been used for multimodality fusion: Software based image registration and hybrid scanners such as PET-CT, PET-MRI, and SPECT-CT among others. While there are intrinsic limitations with both approaches, the main obstacle to the seamless fusion of multiple imaging modalities has been the bulkiness of each individual imager and the conflict of their physical (especially spatial) requirements. To address this challenge, omni-tomography is now unveiled as an emerging direction for biomedical imaging and systems biomedicine

Four novel UCP3 gene variants associated with childhood obesity: effect on fatty acid oxidation and on prevention of triglyceride storage

The objective of the study was to look for uncoupling protein 3 (UCP3) gene variants in early-onset severe childhood obesity and to determine their effect on long-chain fatty acid oxidation and triglyceride storage

Raloxifene inhibits tumor growth and lymph node metastasis in a xenograft model of metastatic mammary cancer

<p>Abstract</p> <p>Background</p> <p>The effects of raloxifene, a novel selective estrogen receptor modulator, were studied in a mouse metastatic mammary cancer model expressing cytoplasmic ERα.</p> <p>Methods</p> <p>Mammary tumors, induced by inoculation of syngeneic BALB/c mice with BJMC3879luc2 cells, were subsequently treated with raloxifene at 0, 18 and 27 mg/kg/day using mini-osmotic pumps.</p> <p>Results</p> <p><it>In vitro </it>study demonstrated that the ERα in BJMC3879luc2 cells was smaller (between 50 and 64 kDa) than the normal-sized ERα (66 kDa) and showed cytoplasmic localization. A statistically significant but weak estradiol response was observed in this cell line. When BJMC3879luc2 tumors were implanted into mice, the ERα mRNA levels were significantly higher in females than in males. <it>In vitro </it>studies showed that raloxifene induced mitochondria-mediated apoptosis and cell-cycle arrest in the G1-phase and a decrease in the cell population in the S-phase. In animal experiments, tumor volumes were significantly suppressed in the raloxifene-treated groups. The multiplicity of lymph node metastasis was significantly decreased in the 27 mg/kg group. Levels of apoptosis were significantly increased in the raloxifene-treated groups, whereas the levels of DNA synthesis were significantly decreased in these groups. No differences in microvessel density in tumors were observed between the control and raloxifene-treated groups. The numbers of dilated lymphatic vessels containing intraluminal tumor cells were significantly reduced in mammary tumors in the raloxifene-treated groups. The levels of ERα mRNA in mammary tumors tended to be decreased in the raloxifene-treated groups.</p> <p>Conclusion</p> <p>These results suggest that the antimetastatic activity of raloxifene in mammary cancer expressing cytoplasmic ERα may be a crucial finding with clinical applications and that raloxifene may be useful as an adjuvant therapy and for the chemoprevention of breast cancer development.</p

Adjunctive raloxifene treatment improves attention and memory in men and women with schizophrenia

There is increasing clinical and molecular evidence for the role of hormones and specifically estrogen and its receptor in schizophrenia. A selective estrogen receptor modulator, raloxifene, stimulates estrogen-like activity in brain and can improve cognition in older adults. The present study tested the extent to which adjunctive raloxifene treatment improved cognition and reduced symptoms in young to middle-age men and women with schizophrenia. Ninety-eight patients with a diagnosis of schizophrenia or schizoaffective disorder were recruited into a dual-site, thirteen-week, randomized, double-blind, placebocontrolled, crossover trial of adjunctive raloxifene treatment in addition to their usual antipsychotic medications. Symptom severity and cognition in the domains of working memory, attention/processing speed, language and verbal memory were assessed at baseline, 6 and 13 weeks. Analyses of the initial 6-week phase of the study using a parallel groups design (with 39 patients receiving placebo and 40 receiving raloxifene) revealed that participants receiving adjunctive raloxifene treatment showed significant improvement relative to placebo in memory and attention/processing speed. There was no reduction in symptom severity with treatment compared with placebo. There were significant carryover effects, suggesting some cognitive benefits are sustained even after raloxifene withdrawal. Analysis of the 13-week crossover data revealed significant improvement with raloxifene only in attention/processing speed. This is the first study to show that daily, oral adjunctive raloxifene treatment at 120 mg per day has beneficial effects on attention/processing speed and memory for both men and women with schizophrenia. Thus, raloxifene may be useful as an adjunctive treatment for cognitive deficits associated with schizophrenia.TW Weickert, D Weinberg, R Lenroot, SV Catts, R Wells, A Vercammen, M O, Donnell, C Galletly, D Liu, R Balzan, B Short, D Pellen, J Curtis, VJ Carr, J Kulkarni, PR Schofield and CS Weicker

Identification of CIITA Regulated Genetic Module Dedicated for Antigen Presentation

The class II trans-activator CIITA is a transcriptional co-activator required for the expression of Major Histocompatibility Complex (MHC) genes. Although the latter function is well established, the global target-gene specificity of CIITA had not been defined. We therefore generated a comprehensive list of its target genes by performing genome-wide scans employing four different approaches designed to identify promoters that are occupied by CIITA in two key antigen presenting cells, B cells and dendritic cells. Surprisingly, in addition to MHC genes, only nine new targets were identified and validated by extensive functional and expression analysis. Seven of these genes are known or likely to function in processes contributing to MHC-mediated antigen presentation. The remaining two are of unknown function. CIITA is thus uniquely dedicated for genes implicated in antigen presentation. The finding that CIITA regulates such a highly focused gene expression module sets it apart from all other transcription factors, for which large-scale binding-site mapping has indicated that they exert pleiotropic functions and regulate large numbers of genes

MRI of the kidney—state of the art

Ultrasound and computed tomography (CT) are modalities of first choice in renal imaging. Until now, magnetic resonance imaging (MRI) has mainly been used as a problem-solving technique. MRI has the advantage of superior soft-tissue contrast, which provides a powerful tool in the detection and characterization of renal lesions. The MRI features of common and less common renal lesions are discussed as well as the evaluation of the spread of malignant lesions and preoperative assessment. MR urography technique and applications are discussed as well as the role of MRI in the evaluation of potential kidney donors. Furthermore the advances in functional MRI of the kidney are highlighted