Phage-inducible chromosomal islands promote genetic variability by blocking phage reproduction and protecting transductants from phage lysis

Funding: This work was supported by the following grants awarded to JPR: MR/M003876/1, MR/S00940X/1 and MR/V000772/1 from the Medical Research Council (MRC, UK; https://mrc.ukri.org); BB/N002873/1, BB/S003835/1 and BB/V002376/1 from the Biotechnology and Biological Sciences Research Council (BBSRC, UK; https://bbsrc.ukri.org); 201531/Z/16/Z from the Wellcome Trust (https://wellcome.org).Phage-inducible chromosomal islands (PICIs) are a widespread family of highly mobile genetic elements that disseminate virulence and toxin genes among bacterial populations. Since their life cycle involves induction by helper phages, they are important players in phage evolution and ecology. PICIs can interfere with the lifecycle of their helper phages at different stages resulting frequently in reduced phage production after infection of a PICI-containing strain. Since phage defense systems have been recently shown to be beneficial for the acquisition of exogenous DNA via horizontal gene transfer, we hypothesized that PICIs could provide a similar benefit to their hosts and tested the impact of PICIs in recipient strains on host cell viability, phage propagation and transfer of genetic material. Here we report an important role for PICIs in bacterial evolution by promoting the survival of phage-mediated transductants of chromosomal or plasmid DNA. The presence of PICIs generates favorable conditions for population diversification and the inheritance of genetic material being transferred, such as antibiotic resistance and virulence genes. Our results show that by interfering with phage reproduction, PICIs can protect the bacterial population from phage attack, increasing the overall survival of the bacterial population as well as the transduced cells. Moreover, our results also demonstrate that PICIs reduce the frequency of lysogenization after temperate phage infection, creating a more genetically diverse bacterial population with increased bet-hedging opportunities to adapt to new niches. In summary, our results identify a new role for the PICIs and highlight them as important drivers of bacterial evolution.Publisher PDFPeer reviewe

FAMIN is a multifunctional purine enzyme enabling the purine nucleotide cycle

Mutations in FAMIN cause arthritis and inflammatory bowel disease in early childhood, and a common genetic variant increases risk for Crohn’s disease and leprosy. We developed an unbiased liquid chromatography mass spectrometry screen for enzymatic activity of this orphan protein. We report that FAMIN phosphorolytically cleaves adenosine into adenine and ribose-1-phosphate. Such activity was considered absent from eukaryotic metabolism. FAMIN and its prokaryotic paralogues additionally have adenosine deaminase, purine nucleoside phosphorylase, and S-methyl-5'-thioadenosine phosphorylase activity, hence combine activities of the namesake enzymes of central purine metabolism. FAMIN enables in macrophages a purine nucleotide cycle (PNC) between adenosine and inosine monophosphate and adenylosuccinate, which consumes aspartate and releases fumarate in a manner involving fatty acid oxidation and ATP-citrate lyase activity. This macrophage PNC synchronises mitochondrial activity with glycolysis by balancing electron transfer to mitochondria, thereby supporting glycolytic activity and promoting oxidative phosphorylation and mitochondrial H+ and phosphate recycling.Includes ERC. Wellcome Trust and MRC

A purine metabolic checkpoint that prevents autoimmunity and autoinflammation.

Still's disease, the paradigm of autoinflammation-cum-autoimmunity, predisposes for a cytokine storm with excessive T lymphocyte activation upon viral infection. Loss of function of the purine nucleoside enzyme FAMIN is the sole known cause for monogenic Still's disease. Here we discovered that a FAMIN-enabled purine metabolon in dendritic cells (DCs) restrains CD4+ and CD8+ T cell priming. DCs with absent FAMIN activity prime for enhanced antigen-specific cytotoxicity, IFNγ secretion, and T cell expansion, resulting in excessive influenza A virus-specific responses. Enhanced priming is already manifest with hypomorphic FAMIN-I254V, for which ∼6% of mankind is homozygous. FAMIN controls membrane trafficking and restrains antigen presentation in an NADH/NAD+-dependent manner by balancing flux through adenine-guanine nucleotide interconversion cycles. FAMIN additionally converts hypoxanthine into inosine, which DCs release to dampen T cell activation. Compromised FAMIN consequently enhances immunosurveillance of syngeneic tumors. FAMIN is a biochemical checkpoint that protects against excessive antiviral T cell responses, autoimmunity, and autoinflammation

FAMIN is a multifunctional purine enzyme enabling the purine nucleotide cycle

Mutations in FAMIN cause arthritis and inflammatory bowel disease in early childhood, and a common genetic variant increases risk for Crohn’s disease and leprosy. We developed an unbiased liquid chromatography mass spectrometry screen for enzymatic activity of this orphan protein. We report that FAMIN phosphorolytically cleaves adenosine into adenine and ribose-1-phosphate. Such activity was considered absent from eukaryotic metabolism. FAMIN and its prokaryotic paralogues additionally have adenosine deaminase, purine nucleoside phosphorylase, and S-methyl-5'-thioadenosine phosphorylase activity, hence combine activities of the namesake enzymes of central purine metabolism. FAMIN enables in macrophages a purine nucleotide cycle (PNC) between adenosine and inosine monophosphate and adenylosuccinate, which consumes aspartate and releases fumarate in a manner involving fatty acid oxidation and ATP-citrate lyase activity. This macrophage PNC synchronises mitochondrial activity with glycolysis by balancing electron transfer to mitochondria, thereby supporting glycolytic activity and promoting oxidative phosphorylation and mitochondrial H+ and phosphate recycling.Includes ERC. Wellcome Trust and MRC

The Muon g-2

The muon anomalous magnetic moment is one of the most precisely measured quantities in particle physics. In a recent experiment at Brookhaven it has been measured with a remarkable 14-fold improvement of the previous CERN experiment reaching a precision of 0.54ppm. Since the first results were published, a persisting "discrepancy" between theory and experiment of about 3 standard deviations is observed. It is the largest "established" deviation from the Standard Model seen in a "clean" electroweak observable and thus could be a hint for New Physics to be around the corner. This deviation triggered numerous speculations about the possible origin of the "missing piece" and the increased experimental precision animated a multitude of new theoretical efforts which lead to a substantial improvement of the prediction of the muon anomaly a_mu=(g_mu-2)/2. The dominating uncertainty of the prediction, caused by strong interaction effects, could be reduced substantially, due to new hadronic cross section measurements in electron-positron annihilation at low energies. Also the recent electron g-2 measurement at Harvard contributes substantially to the progress in this field, as it allows for a much more precise determination of the fine structure constant alpha as well as a cross check of the status of our theoretical understanding.Comment: 134 pages, 68 figure

Dendritic polyglycerol cyclodextrin amphiphiles and their self-assembled architectures to transport hydrophobic guest molecules

Here we report for the first time a microwave assisted synthesis of polyglycerol dendron functionalized cyclodextrins (CD) with hydrophobic tails. These amphiphilic CDs consist of seven polyglycerol dendrons and fourteen alkyl chains on the primary and secondary rims of the cyclodextrin core, respectively. They self-assemble to form nanostructures in aqueous solutions and efficiently encapsulate hydrophobic aromatic guests. The size and shape of the self-assemblies and also their ability to encapsulate guest molecules depend on the generation of conjugated polyglycerol dendrons