Neuronal death in the central nervous system demonstrates a non-fibrin substrate for plasmin

Mice deficient for plasminogen exhibit a variety of pathologies, all of which examined to date are reversed when the animals are also made fibrin(ogen) deficient. These results suggested that the predominant, and perhaps exclusive, physiological role of plasminogen is clearance of fibrin. Plasminogen-deficient mice also display resistance to excitotoxin-induced neurodegeneration, in contrast with wild-type mice, which are sensitive. Based on the genetic interaction between plasminogen and fibrinogen, we investigated whether resistance to neuronal cell death in the plasminogen-deficient mice is dependent on fibrin(ogen). Unexpectedly, mice lacking both plasminogen and fibrinogen are resistant to neurodegeneration to levels comparable to plasminogen-deficient mice. Therefore, plasmin acts on substrates other than fibrin during experimental neuronal degeneration, and may function similarly in other pathological settings in the central nervous system.

Hsf1 and Hsp90 orchestrate temperature-dependent global transcriptional remodelling and chromatin architecture in Candida albicans

We thank Karim Gharbi and Urmi Trivedi for their assistance with RNA sequencing, carried out in the GenePool genomics facility (University of Edinburgh). We also thank Susan Fairley and Eduardo De Paiva Alves (Centre for Genome Enabled Biology and Medicine, University of Aberdeen) for help with the initial bioinformatics analysis. We thank Aaron Mitchell for kindly providing the ALS3 mutant, Julian Naglik for the gift of TR146 cells, and Jon Richardson for technical assistance. We thank the Genomics and Bioinformatics core of the Faculty of Health Sciences for Next Generation Sequencing and Bioinformatics support, the Information and Communication Technology Office at the University of Macau for providing access to a High Performance Computer and Jacky Chan and William Pang for their expert support on the High Performance Computer. Finally, we thank Amanda Veri for generating CaLC2928. M.D.L. is supported by a Sir Henry Wellcome Postdoctoral Fellowship (Wellcome Trust 096072), R.A.F. by a Wellcome Trust-Massachusetts Institute of Technology (MIT) Postdoctoral Fellowship, L.E.C. by a Canada Research Chair in Microbial Genomics and Infectious Disease and by Canadian Institutes of Health Research Grants MOP-119520 and MOP-86452, A.J. P.B. was supported by the UK Biotechnology and Biological Sciences Research Council (BB/F00513X/1) and by the European Research Council (ERC-2009-AdG-249793-STRIFE), KHW is supported by the Science and Technology Development Fund of Macau S.A.R (FDCT) (085/2014/A2) and the Research and Development Administrative Office of the University of Macau (SRG2014-00003-FHS) and R.T.W. by the Burroughs Wellcome fund and NIH R15AO094406. Data availability RNA-sequencing data sets are available at ArrayExpress (www.ebi.ac.uk) under accession code E-MTAB-4075. ChIP-seq data sets are available at the NCBI SRA database (http://www.ncbi.nlm.nih.gov) under accession code SRP071687. The authors declare that all other data supporting the findings of this study are available within the article and its supplementary information files, or from the corresponding author upon request.

Evidence for rapid disappearance of initially expanded HIV-specific CD8+ T cell clones during primary HIV infection

Down-regulation of the initial burst of viremia during primary HIV infection is thought to be mediated predominantly by HIV-specific cytotoxic T lymphocytes, and the appearance of this response is associated with major perturbations of the T cell receptor repertoire. Changes in the T cell receptor repertoire of virus-specific cytotoxic T lymphocytes were analyzed in patients with primary infection to understand the failure of the cellular immune response to control viral spread and replication. This analysis demonstrated that a significant number of HIV-specific T cell clones involved in the primary immune response rapidly disappeared. The disappearance was not the result of mutations in the virus epitopes recognized by these clones. Evidence is provided that phenomena such as high-dose tolerance or clonal exhaustion might be involved in the disappearance of these monoclonally expanded HIV-specific cytotoxic T cell clones. These findings should provide insights into how HIV, and possibly other viruses, elude the host immune response during primary infection.

Restricted structural gene polymorphism in the Mycobacterium tuberculosis complex indicates evolutionarily recent global dissemination

One-third of humans are infected with Mycobacterium tuberculosis, the causative agent of tuberculosis. Sequence analysis of two megabases in 26 structural genes or loci in strains recovered globally discovered a striking reduction of silent nucleotide substitutions compared with other human bacterial pathogens. The lack of neutral mutations in structural genes indicates that M. tuberculosis is evolutionarily young and has recently spread globally. Species diversity is largely caused by rapidly evolving insertion sequences, which means that mobile element movement is a fundamental process generating genomic variation in this pathogen. Three genetic groups of M. tuberculosis were identified based on two polymorphisms that occur at high frequency in the genes encoding catalase-peroxidase and the A subunit of gyrase. Group 1 organisms are evolutionarily old and allied with M. bovis, the cause of bovine tuberculosis. A subset of several distinct insertion sequence IS6110 subtypes of this genetic group have IS6110 integrated at the identical chromosomal insertion site, located between dnaA and dnaN in the region containing the origin of replication. Remarkably, study of ≈6,000 isolates from patients in Houston and the New York City area discovered that 47 of 48 relatively large case clusters were caused by genotypic group 1 and 2 but not group 3 organisms. The observation that the newly emergent group 3 organisms are associated with sporadic rather than clustered cases suggests that the pathogen is evolving toward a state of reduced transmissability or virulence.

Statistical modelling of variability in sediment-water nutrient and oxygen fluxes

Peer reviewed

Complementation of sporulation and motility defects in a prokaryote by a eukaryotic GTPase

The complex prokaryote, Myxococcus xanthus, undergoes a program of multicellular development when starved for nutrients, culminating in sporulation. M. xanthus makes MglA, a 22-kDa, soluble protein that is required for both multicellular development and gliding motility. MglA is similar in sequence to the Saccharomyces cerevisiae SAR1 protein, a member of the Ras/Rab/Rho superfamily of small eukaryotic GTPases. The SAR1 gene, when integrated into the M. xanthus genome, complements the sporulation defect of a ΔmglA strain. A forward, second-site mutation on the M. xanthus chromosome, rpm, in combination with SAR1, restores fruiting body morphogenesis and gliding motility to a ΔmglA strain. The result that the rpm mutation suppresses the substitution of SAR1 for mglA suggests that Sar1p interacts with other M. xanthus proteins to control the motility-dependent aggregation of cells during development.

Peropsin, a novel visual pigment-like protein located in the apical microvilli of the retinal pigment epithelium

A visual pigment-like protein, referred to as peropsin, has been identified by large-scale sequencing of cDNAs derived from human ocular tissues. The corresponding mRNA was found only in the eye, where it is localized to the retinal pigment epithelium (RPE). Peropsin immunoreactivity, visualized by light and electron microscopy, localizes the protein to the apical face of the RPE, and most prominently to the microvilli that surround the photoreceptor outer segments. These observations suggest that peropsin may play a role in RPE physiology either by detecting light directly or by monitoring the concentration of retinoids or other photoreceptor-derived compounds.