Ancestral function and diversification of a horizontally acquired oomycete carboxylic acid transporter

This is the author accepted manuscript. The final version is available from OUP via the DOI in this recordHorizontal gene transfer (HGT) can equip organisms with novel genes, expanding the repertoire of genetic material available for evolutionary innovation and allowing recipient lineages to colonise new environments. However, few studies have characterised the functions of HGT genes experimentally or examined post-acquisition functional divergence. Here we report the use of ancestral sequence reconstruction and heterologous expression in Saccharomyces cerevisiae to examine the evolutionary history of an oomycete transporter gene family that was horizontally acquired from fungi. We demonstrate that the inferred ancestral oomycete HGT transporter proteins and their extant descendants are predominantly localised to the plasma membrane when expressed in yeast, and that they transport dicarboxylic acids which are intermediates of the tricarboxylic acid cycle. The substrate specificity profile of the most ancestral protein has largely been retained throughout the radiation of oomycetes, including in both plant and animal pathogens and in a free-living saprotroph, indicating that the ancestral HGT transporter function has been maintained by selection across a range of different lifestyles. No evidence of neofunctionalization in terms of substrate specificity was detected for different HGT transporter paralogues which have different patterns of temporal expression. However, a striking expansion of substrate range was observed for one plant pathogenic oomycete, with a HGT derived paralogue from Pythium aphanidermatum encoding a protein that enables tricarboxylic acid uptake in addition to dicarboxylic acid uptake. This demonstrates that HGT acquisitions can provide functional additions to the recipient proteome as well as the foundation material for the evolution of new protein functions.This work was supported by a Philip Leverhulme Award to T. A. R. We acknowledge related project funding from the Gordon and Betty Moore Foundation (GBMF5514). T.A.R. is supported by a Royal Society University Research Fellowshi

Your space or mine? : Mapping self in time

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Optically trapped bacteria pairs reveal discrete motile response to control aggregation upon cell–cell approach

Aggregation of bacteria plays a key role in the formation of many biofilms. The critical first step is cell–cell approach, and yet the ability of bacteria to control the likelihood of aggregation during this primary phase is unknown. Here, we use optical tweezers to measure the force between isolated Bacillus subtilis cells during approach. As we move the bacteria towards each other, cell motility (bacterial swimming) initiates the generation of repulsive forces at bacterial separations of ~3 μm. Moreover, the motile response displays spatial sensitivity with greater cell–cell repulsion evident as inter-bacterial distances decrease. To examine the environmental influence on the inter-bacterial forces, we perform the experiment with bacteria suspended in Tryptic Soy Broth, NaCl solution and deionised water. Our experiments demonstrate that repulsive forces are strongest in systems that inhibit biofilm formation (Tryptic Soy Broth), while attractive forces are weak and rare, even in systems where biofilms develop (NaCl solution). These results reveal that bacteria are able to control the likelihood of aggregation during the approach phase through a discretely modulated motile response. Clearly, the force-generating motility we observe during approach promotes biofilm prevention, rather than biofilm formation

Selective Affimers Recognise the BCL‐2 Family Proteins BCL‐xL and MCL‐1 through Noncanonical Structural Motifs

The BCL‐2 family is a challenging group of proteins to target selectively due to sequence and structural homologies across the family. Selective ligands for the BCL‐2 family regulators of apoptosis are useful as probes to understand cell biology and apoptotic signalling pathways, and as starting points for inhibitor design. We have used phage display to isolate Affimer reagents (non‐antibody‐binding proteins based on a conserved scaffold) to identify ligands for MCL‐1, BCL‐xL, BCL‐2, BAK and BAX, then used multiple biophysical characterisation methods to probe the interactions. We established that purified Affimers elicit selective recognition of their target BCL‐2 protein. For anti‐apoptotic targets BCL‐xL and MCL‐1, competitive inhibition of their canonical protein‐protein interactions is demonstrated. Co‐crystal structures reveal an unprecedented mode of molecular recognition; where a BH3 helix is normally bound, flexible loops from the Affimer dock into the BH3 binding cleft. Moreover, the Affimers induce a change in the target proteins towards a desirable drug‐bound‐like conformation. These proof‐of‐concept studies indicate that Affimers could be used as alternative templates to inspire the design of selective BCL‐2 family modulators and more generally other protein‐protein interaction inhibitors

30 days wild: development and evaluation of a large-scale nature engagement campaign to improve well-being

There is a need to increase people’s engagement with and connection to nature, both for human well-being and the conservation of nature itself. In order to suggest ways for people to engage with nature and create a wider social context to normalise nature engagement, The Wildlife Trusts developed a mass engagement campaign, 30 Days Wild. The campaign asked people to engage with nature every day for a month. 12,400 people signed up for 30 Days Wild via an online sign-up with an estimated 18,500 taking part overall, resulting in an estimated 300,000 engagements with nature by participants. Samples of those taking part were found to have sustained increases in happiness, health, connection to nature and pro-nature behaviours. With the improvement in health being predicted by the improvement in happiness, this relationship was mediated by the change in connection to nature

Proteomic Insights into the Hidden World of Phloem Sap Feeding

The physical interface between a phloem-feeding insect and its host plant is a single cell buried deep within the plant tissue. As such, the molecular interactions between these notorious agricultural pests and the crop plants upon which they feed are diffi cult to study. ‘Omic’ technologies have proved crucial in revealing some of the fascinating detail of the molecular interplay between these partners. Here we review the role of proteomics in identifying putative components of the secreted saliva of phloem-feeding insects, particularly aphids, and discuss the limited knowledge concerning the function of these proteins

Latent HIV in primary T lymphocytes is unresponsive to histone deacetylase inhibitors

Recently, there is considerable interest in the field of anti-HIV therapy to identify and develop chromatin-modifying histone deacetylase (HDAC) inhibitors that can effectively reactivate latent HIV in patients. The hope is that this would help eliminate cells harboring latent HIV and achieve an eventual cure of the virus. However, how effectively these drugs can stimulate latent HIVs in quiescent primary CD4 T cells, despite their relevant potencies demonstrated in cell line models of HIV latency, is not clear. Here, we show that the HDAC inhibitors valproic acid (VPA) and trichostatin A (TSA) are unable to reactivate HIV in latently infected primary CD4 T cells generated in the H80 co-culture system. This raises a concern that the drugs inhibiting HDAC function alone might not be sufficient for stimulating latent HIV in resting CD4 T cells in patients and not achieve any anticipated reduction in the pool of latent reservoirs

Environmental Factors in the Relapse and Recurrence of Inflammatory Bowel Disease:A Review of the Literature

The causes of relapse in patients with Crohn's disease (CD) and ulcerative colitis (UC) are largely unknown. This paper reviews the epidemiological and clinical data on how medications (non-steroidal anti-inflammatory drugs, estrogens and antibiotics), lifestyle factors (smoking, psychological stress, diet and air pollution) may precipitate clinical relapses and recurrence. Potential biological mechanisms include: increasing thrombotic tendency, imbalances in prostaglandin synthesis, alterations in the composition of gut microbiota, and mucosal damage causing increased permeability