Summer research vacation competition: An opportunity for post-docs and undergraduates

Background: Being a post-doctoral researcher is not necessarily a happy time full of opportunities for progression and promotion (Grinstein & Treister, 2018). The postdoctoral system has been described as broken (Powell, 2015). Whilst postdoctoral positions may be thought of as opportunities for research post-PhD (McAlpine & Akerlind, 2010), they are often ignored in the literature (Scaffidi & Berman, 2011). We know there is a drop off in interest in pursuing a research career as students progress through higher education (Roach, 2017). However, research into academic research and researchers often focuses on ‘tenured’ academics; how they might go about developing opportunities for research, collaborations with others, and balancing it with teaching and other commitments (Brew & Lucas, 2009). Reflecting on research might only happen from the PI’s perspective (Shakespeare, Atkinson, & French, 1993). Being in “the limbo of a postdoctoral research post” (Becher & Trowler, 1989, p. 137) is often seen as a required stage in the development of a successful academic career. However, postdocs do not always have a clear career plan to develop an academic career (Sauermann & Roach, 2016). Developing into a successful academic depends on many factors (van Balena et al, 2012). Research is seen as a game (Lucas, 2006), particularly in the context of the REF. However, achieving excellent world-leading research depends on postdocs, to carry out the work, and to form the research environment, and as such if we want to develop research we need to develop researchers at every level (Vitae, 2017). A supportive atmosphere is the most important criterion in enhancing life satisfaction and maintaining positivity about a research career for postdocs (Grinstein & Treister, 2018)

A REPORT BY THE ALL - PARTY PARLIAMENTARY GROUP ON A FIT AND HEALTHY CHILDHOOD THE IMPACT OF SOCIAL AND ECONOMIC INEQUALITIES ON CHILDREN’S HEALTH

A child born into circumstances of social and economic inequality in the 21st century United Kingdom will start life with one hand tied behind their back. Nowhere is the disparity of experience more marked than in that of health and this, in turn, impacts the entire life course. In the same way that priority is given to securing the national infrastructure, prioritising the health of children from all areas and in all circumstances from the outset would therefore seem to be prudent rather than profligate. Yet as this Report demonstrates,successive Governments have skimped rather thansaved; failedto build upon existing policy and played a costly policy game of ‘catching up later’ instead of deploying the early ntervention me asures that are cheaper andmore effective in the long term

TLR-4 ligation of dendritic cells is sufficient to drive pathogenic T cell function in experimental autoimmune encephalomyelitis

<p>Abstract</p> <p>Background</p> <p>Experimental autoimmune encephalomyelitis (EAE) depends on the initial activation of CD4⁺ T cells responsive to myelin autoantigens. The key antigen presenting cell (APC) population that drives the activation of naïve T cells most efficiently is the dendritic cell (DC). As such, we should be able to trigger EAE by transfer of DC that can present the relevant autoantigen(s). Despite some sporadic reports, however, models of DC-driven EAE have not been widely adopted. We sought to test the feasibility of this approach and whether activation of the DC by toll-like receptor (TLR)-4 ligation was a sufficient stimulus to drive EAE.</p> <p>Findings</p> <p>Host mice were seeded with myelin basic protein (MBP)-reactive CD4+ T cells and then were injected with DC that could present the relevant MBP peptide which had been exposed to lipopolysaccharide as a TLR-4 agonist. We found that this approach induced robust clinical signs of EAE.</p> <p>Conclusions</p> <p>DC are sufficient as APC to effectively drive the differentiation of naïve myelin-responsive T cells into autoaggressive effector T cells. TLR-4-stimulation can activate the DC sufficiently to deliver the signals required to drive the pathogenic function of the T cell. These models will allow the dissection of the molecular requirements of the initial DC-T cell interaction in the lymphoid organs that ultimately leads to autoimmune pathology in the central nervous system.</p

Fluorescence and Absorption Detected Magnetic Resonance of Membranes from the Green Sulfur Bacterium Chlorobium limicola . Full Assignment of Detected Triplet States

Optically detected magnetic resonance of chlorosomes-containing membranes from the green sulfur bacterium Chlorobium limicola has been performed both by fluorescence and absorption detection. Triplet states localized in the chlorosomes and in the FMO complex have been characterized. After chemical reduction with dithionite followed by illumination at 200 K, a recombination triplet state localized in the primary donor P840 becomes populated under illumination at low temperature. A reaction center triplet state characterized by slightly different ZFS parameters, grows up irreversibly after prolonged illumination at low temperature in the presence of reductant. We were able to obtain the T−S spectra of the FMO complex and of the primary donor P840 in their native environment and to compare them to the spectra obtained in isolated complexes previously published, revealing differences in the spectra. Fluorescence detected magnetic resonance measurements demonstrate that the BChl c antenna pigments are connected via energy transfer to the BChl a molecules at the low temperature of the measurements (1.8 K) and that all the pigments carrying the triplet states are sensitive to the redox treatment. Dithionite reduction, in fact, induces an enhancement of the BChl c and, at a major extent, of the BChl a fluorescence yield accompanied by an increase of the yield of all the triplet states of the pigments. Evidence for the presence of BChl c excited states quenchers in the core chlorosome and for their selective effect at low temperature is provided, and the location of the quenchers close to BChl c molecules absorbing at longer wavelengths discussed.</p

CysG Structure Reveals Tetrapyrrole-Binding Features and Novel Regulation of Siroheme Biosynthesis

Sulfur metabolism depends on the iron-containing porphinoid siroheme. In Salmonella enterica, the S-adenosyl-L-methionine (SAM)-dependent bismethyltransferase, dehydrogenase and ferrochelatase, CysG, synthesizes siroheme from uroporphyrinogen III (uro’gen III). The reactions mediated by CysG encompass two branchpoint intermediates in tetrapyrrole biosynthesis, diverting flux first from protoporphyrin IX biosynthesis and then from cobalamin (vitamin B12) biosynthesis. We determined the first structure of this multifunctional siroheme synthase by X-ray crystallography. CysG is a homodimeric gene fusion product containing two structurally independent modules: a bismethyltransferase and a dual-function dehydrogenasechelatase. The methyltransferase active site is a deep groove with a hydrophobic patch surrounded by hydrogen bond donors. This asymmetric arrangement of amino acids may be important in directing substrate binding. Notably, our structure shows that CysG is a phosphoprotein. From mutational analysis of the post-translationally modified serine, we suggest a conserved role for phosphorylation in inhibiting dehydrogenase activity and modulating metabolic flux between siroheme and cobalamin pathways

Iron–sulfur cluster dynamics in biotin synthase: A new [2Fe–2S]1+ cluster

Biotin synthase (BioB) catalyses the final step in the biosynthesis of biotin. Aerobically purified biotin synthase contains one [2Fe–2S]2+ cluster per monomer. However, active BioB contains in addition a [4Fe–4S]2+ cluster which can be formed either by reconstitution with iron and sulfide, or on reduction with sodium dithionite. Here, we use EPR spectroscopy to show that mutations in the conserved YNHNLD sequence of Escherichia coli BioB affect the formation and stability of the [4Fe–4S]1+ cluster on reduction with dithionite and report the observation of a new [2Fe–2S]1+ cluster. These results serve to illustrate the dynamic nature of iron–sulfur clusters in biotin synthase and the role played by the protein in cluster interconversion

The structure of Saccharomyces cerevisiae Met8p, a bifunctional dehydrogenase and ferrochelatase.

Sirohaem is a tetrapyrrole-derived prosthetic group that is required for the essential assimilation of sulfur and nitrogen into all living systems as part of the sulfite and nitrite reductase systems. The final two steps in the biosynthesis of sirohaem involve a beta-NAD(+)-dependent dehydrogenation of precorrin-2 to generate sirohydrochlorin followed by ferrochelation to yield sirohaem. In Saccharomyces cerevisiae, Met8p is a bifunctional enzyme that carries out both of these reactions. Here, we report the 2.2 A resolution crystal structure of Met8p, which adopts a novel fold that bears no resemblance to the previously determined structures of cobalt- or ferro-chelatases. Analysis of mutant proteins suggests that both catalytic activities share a single active site, and that Asp141 plays an essential role in both dehydrogenase and chelatase processes

Biochemical and Structural Insights into Bacterial Organelle Form and Biogenesis

Many heterotrophic bacteria have the ability to make polyhedral structures containing metabolic enzymes that are bounded by a unilamellar protein shell (metabolosomes or enterosomes). These bacterial organelles contain enzymes associated with a specific metabolic process (e.g. 1,2-propanediol or ethanolamine utilization). We show that the 21 gene regulon specifying the pdu organelle and propanediol utilization enzymes from Citrobacter freundii is fully functional when cloned in Escherichia coli, both producing metabolosomes and allowing propanediol utilization. Genetic manipulation of the level of specific shell proteins resulted in the formation of aberrantly shaped metabolosomes, providing evidence for their involvement as delimiting entities in the organelle. This is the first demonstration of complete recombinant metabolosome activity transferred in a single step and supports phylogenetic evidence that the pdu genes are readily horizontally transmissible. One of the predicted shell proteins (PduT) was found to have a novel Fe-S center formed between four protein subunits. The recombinant model will facilitate future experiments establishing the structure and assembly of these multiprotein assemblages and their fate when the specific metabolic function is no longer required