Association between fetal abdominal growth trajectories, maternal metabolite signatures early in pregnancy, and childhood growth and adiposity: prospective observational multinational INTERBIO-21st fetal study

New study from the Bowman Lab published in eLife defines a novel nuclear translocation pathway involving the specific import receptor Importin-5 and the histone chaperone NASP that specialise in ferrying monomeric histones to the nucleus.

Read the paper hereLink opens in a new window.

Nanoparticles have found widespread use in diagnostics and have been suggested for e.g. drug delivery. Chemists can now fine tune the nanoparticle surface to e.g target cell types. However, what a cell 'sees' is not what is made by the chemists, but rather a complex mixture of proteins which ‘foul’ the surface, recruited from the blood, termed the protein corona. There has been extensive research into the proteins which make up the corona, but the glycans on these proteins have received less attention. This is a major problem, as > 50 % of our proteome is glycosylated, and hence investigating a nanoparticle’s protein corona, without considering the glycans, does not give an accurate picture.

In our latest work, we investigate the impact of the glycoprotein corona on how polymer-coated nanoparticles bind lectins. We show that serum proteins bring significant sialic acids to the particle surface. The impact of this, is that the particles can bind additional lectins (which were not intended) as well as those which are intended. Finally, we show that 'blocking' the surface does reduce the amount of protein, but sufficient glycans remain to cause off-target binding. These results will help guide the next generation of nanoparticle sensing and delivery agents.
Read the paper hereLink opens in a new window.

The use of nanoparticles as drug delivery vehicles is well established. Numerous studies have investigated the impact of size, shape, charge, and surface functionality of nanoparticles on mammalian cellular uptake. Rigidity, however, has been studied to a far lesser extent, and its effects are still unclear. Here, in a collaboration between the Chemistry and BMS, this is systematically explored.

Three different polymeric core rigidities were tested: hard, medium and soft using two 50 and 100 nm diameter particles. Cellular uptake studies indicated that 100nm softer particles are taken up faster and 3-fold more into mammalian cells compared to harder nanoparticles, probably via major differences in the cellular uptake pathways. However, 50 nm derivatives did not show any appreciable differences in uptake efficiency suggesting that rigidity as a parameter for nanomaterials in the biological regime might be size dependent.

Read the paper here.

In a recent study published in Cell Reports, teams from University College London and Warwick Medical School describe how protein fusion of two epigenetic modulators, JAZF1 and SUZ12, causes oncogenesis in human endometrial stromal cells by disrupting the composition of the polycomb repressive complex 2 (PRC2), resulting in aberrant histone modification, gene expression and cell differentiation (decidualization). The results reveal how dysregulation of PRC2 drives the emergence of low-grade endometrial stromal sarcomas in the womb, which provide opportunities to improve the treatment of this disease.

Read the paper here.

All cells must accurately separate their chromosomes during mitosis to avoid errors that are associated with cancer development, reproductive failure and even ageing. This feat is accomplished by the mitotic spindle – this microtubule-based machine has a bipolar geometry and contains hundreds of protein components. A subset of microtubules form bundles that make contact with kinetochores on the chromosome (these are called K-fibres). The growth and shrinkage of these microtubules, through addition and loss of tubulin, is coupled to the hydrolysis of GTP: this powers chromosome movement. Previous work identified a protein called HURP (hepatoma up-regulated protein) that forms distinctive stripes on each half spindle (see schematic). Here, through collaboration with University of Geneva, we identified a new region within the mitotic spindle, termed “HURP-gap”. This HURP free region of the K-fibre is located between the stripe and the kinetochore.

Discovery: How do organs reach a specific size during development? The Hippo/YAP pathway has been identified as a critical regulator of organ size control. It also plays an important role in homeostasis and cancer progression, in part due to its mechanosensitive response. Here, the Saunders lab have developed an optogenetic version of YAP (optoYAP) that enables its localisation to the nucleus to be tightly controlled in both space and time. This enables targeted perturbation of the pathway, with potential applications to wound healing and regeneration.
Read the paper hereLink opens in a new window.

The GibsonGroup are developing macromolecular (polymer) cryoprotectants to enable next-generation cell based therapies, and to simplify cell-based assays. A key feature identified in the teams most potent materials is a mixture of cationic/anionic charges on the side chain, but the exact mechanism of action is under investigation. In this latest work the team explored sulphoxide (‘DMSO like’) side chains, which are actually highly polarised with S+-O- character. The team also explore N-oxide polymers which have similar charged character. Using a range of phyical and biochemical assays the team investigated if these motifs could aid in cryopreservation.
Read the paper hereLink opens in a new window.

We have now published back to back two papers on the so called anthrax “cross over strain Bacillus cereus G9241. The first paper (From cereus to anthrax and back again: The role of the PlcR regulator in the “cross-over” strain Bacillus cereus G9241) has already been highlighted. This current paper is titled, “The influence of extrachromosomal elements in the anthrax “cross-over” strain Bacillus cereus G9241.”

The work investigates the contribution of anthrax-like plasmids and a lysogenic phagemid to the pathogenic potential of the normally relatively harmless Bacillus cereus. We investigated the role of temperature and carriage of the pBCXO1 plasmid (which is homologous to the pXO1 anthrax toxin plasmid) in regulation of chromosomal genes, heavily affecting metabolism. In addition we have shown that sporulation of G9241 is very rapid at 37’C, which is characteristic of B. anthracis but unlike the ancestral B. cereus strains. Finally we isolated phagemid virions which are produced at 37’C and visualised them with electron microscopy.

Read the paper here.

In our recent paper “From cereus to anthrax and back again: The role of the PlcR regulator in the “cross-over” strain Bacillus cereus G9241” we have investigated how a normally low risk Bacillus cereus strain has evolved to mimic Bacillus anthracis, the causative agent of the highly feared lethal anthrax infection. The B. cereus G9241 strain is one of several relatively recent isolates that are termed “anthrax cross over strains” that intriguingly seem to preferentially infect metal workers in the USA (welders / millers). These strains are of particular concern as, unlike B. anthracis proper, they can switch between a form that can survive and replicate in the environment using invertebrate hosts and the more lethal mammalian infective anthrax like form. B. anthracis must pass from mammalian host to mammalian host as a spore form thus somewhat limiting its spread. This is due to a loss of function mutation in a key regulator protein named PlcR, which in all other B. cereus sensu lato group strains allows for survival outside of a mammalian host. Our work has identified the specific mechanism by which G9241 can switch on and off the PlcR regulation endowing it with a “Dr. Jekyll or Mr. Hyde” like life cycle. This work was a culmination of a Marie Curie fellow, 3 PhD students and one postdoc and was supported by MoD Porton Down DSTL funding and advice, for which we are very grateful.

Read the paper here.