A Fundamental Regulatory Mechanism Operating through OmpR and DNA Topology Controls Expression of Salmonella Pathogenicity Islands SPI-1 and SPI-2

DNA topology has fundamental control over the ability of transcription factors to access their target DNA sites at gene promoters. However, the influence of DNA topology on protein–DNA and protein–protein interactions is poorly understood. For example, relaxation of DNA supercoiling strongly induces the well-studied pathogenicity gene ssrA (also called spiR) in Salmonella enterica, but neither the mechanism nor the proteins involved are known. We have found that relaxation of DNA supercoiling induces expression of the Salmonella pathogenicity island (SPI)-2 regulator ssrA as well as the SPI-1 regulator hilC through a mechanism that requires the two-component regulator OmpR-EnvZ. Additionally, the ompR promoter is autoregulated in the same fashion. Conversely, the SPI-1 regulator hilD is induced by DNA relaxation but is repressed by OmpR. Relaxation of DNA supercoiling caused an increase in OmpR binding to DNA and a concomitant decrease in binding by the nucleoid-associated protein FIS. The reciprocal occupancy of DNA by OmpR and FIS was not due to antagonism between these transcription factors, but was instead a more intrinsic response to altered DNA topology. Surprisingly, DNA relaxation had no detectable effect on the binding of the global repressor H-NS. These results reveal the underlying molecular mechanism that primes SPI genes for rapid induction at the onset of host invasion. Additionally, our results reveal novel features of the archetypal two-component regulator OmpR. OmpR binding to relaxed DNA appears to generate a locally supercoiled state, which may assist promoter activation by relocating supercoiling stress-induced destabilization of DNA strands. Much has been made of the mechanisms that have evolved to regulate horizontally-acquired genes such as SPIs, but parallels among the ssrA, hilC, and ompR promoters illustrate that a fundamental form of regulation based on DNA topology coordinates the expression of these genes regardless of their origins

The impact of viral mutations on recognition by SARS-CoV-2 specific T cells.

We identify amino acid variants within dominant SARS-CoV-2 T cell epitopes by interrogating global sequence data. Several variants within nucleocapsid and ORF3a epitopes have arisen independently in multiple lineages and result in loss of recognition by epitope-specific T cells assessed by IFN-γ and cytotoxic killing assays. Complete loss of T cell responsiveness was seen due to Q213K in the A∗01:01-restricted CD8+ ORF3a epitope FTSDYYQLY207-215; due to P13L, P13S, and P13T in the B∗27:05-restricted CD8+ nucleocapsid epitope QRNAPRITF9-17; and due to T362I and P365S in the A∗03:01/A∗11:01-restricted CD8+ nucleocapsid epitope KTFPPTEPK361-369. CD8+ T cell lines unable to recognize variant epitopes have diverse T cell receptor repertoires. These data demonstrate the potential for T cell evasion and highlight the need for ongoing surveillance for variants capable of escaping T cell as well as humoral immunity.This work is supported by the UK Medical Research Council (MRC); Chinese Academy of Medical Sciences(CAMS) Innovation Fund for Medical Sciences (CIFMS), China; National Institute for Health Research (NIHR)Oxford Biomedical Research Centre, and UK Researchand Innovation (UKRI)/NIHR through the UK Coro-navirus Immunology Consortium (UK-CIC). Sequencing of SARS-CoV-2 samples and collation of data wasundertaken by the COG-UK CONSORTIUM. COG-UK is supported by funding from the Medical ResearchCouncil (MRC) part of UK Research & Innovation (UKRI),the National Institute of Health Research (NIHR),and Genome Research Limited, operating as the Wellcome Sanger Institute. T.I.d.S. is supported by a Well-come Trust Intermediate Clinical Fellowship (110058/Z/15/Z). L.T. is supported by the Wellcome Trust(grant number 205228/Z/16/Z) and by theUniversity of Liverpool Centre for Excellence in Infectious DiseaseResearch (CEIDR). S.D. is funded by an NIHR GlobalResearch Professorship (NIHR300791). L.T. and S.C.M.are also supported by the U.S. Food and Drug Administration Medical Countermeasures Initiative contract75F40120C00085 and the National Institute for Health Research Health Protection Research Unit (HPRU) inEmerging and Zoonotic Infections (NIHR200907) at University of Liverpool inpartnership with Public HealthEngland (PHE), in collaboration with Liverpool School of Tropical Medicine and the University of Oxford.L.T. is based at the University of Liverpool. M.D.P. is funded by the NIHR Sheffield Biomedical ResearchCentre (BRC – IS-BRC-1215-20017). ISARIC4C is supported by the MRC (grant no MC_PC_19059). J.C.K.is a Wellcome Investigator (WT204969/Z/16/Z) and supported by NIHR Oxford Biomedical Research Centreand CIFMS. The views expressed are those of the authors and not necessarily those of the NIHR or MRC

fisheries and tourism social economic and ecological trade offs in coral reef systems

Coastal communities are exerting increasingly more pressure on coral reef ecosystem services in the Anthropocene. Balancing trade-offs between local economic demands, preservation of traditional values, and maintenance of both biodiversity and ecosystem resilience is a challenge for reef managers and resource users. Consistently, growing reef tourism sectors offer more lucrative livelihoods than subsistence and artisanal fisheries at the cost of traditional heritage loss and ecological damage. Using a systematic review of coral reef fishery reconstructions since the 1940s, we show that declining trends in fisheries catch and fish stocks dominate coral reef fisheries globally, due in part to overfishing of schooling and spawning-aggregating fish stocks vulnerable to exploitation. Using a separate systematic review of coral reef tourism studies since 2013, we identify socio-ecological impacts and economic opportunities associated to the industry. Fisheries and tourism have the potential to threaten the ecological stability of coral reefs, resulting in phase shifts toward less productive coral-depleted ecosystem states. We consider whether four common management strategies (unmanaged commons, ecosystem-based management, co-management, and adaptive co-management) fulfil ecological conservation and socioeconomic goals, such as living wage, job security, and maintenance of cultural traditions. Strategies to enforce resource exclusion and withhold traditional resource rights risk social unrest; thus, the coexistence of fisheries and tourism industries is essential. The purpose of this chapter is to assist managers and scientists in their responsibility to devise implementable strategies that protect local community livelihoods and the coral reefs on which they rely

Sorry everyone, but it didn't work (p = 0.06)

The more or less ubiquitous use of Fisher-type statistics in quantitative/numeric evaluations of drug and alcohol education initiatives takes place within the context of a literature of long standing which suggests there are areas in which null hypothesis testing and the use of conventional cut-off points (i.e. the 1% and 5% probability levels) are inappropriate. This literature is largely ignored. The paper identifies some of these issues in terms of their relevance to the problems of evaluation of drug/alcohol programmes. The paper argues that the qualitative approach does not solve these problems but merely by-passes them, as well as being unsatisfactory in a number of ways. Thus, it is concluded that there is a pressing need for change in the type of quantitative approach adopted. Suggestions are made for a variety of exploratory methods, still involving broadly numerical analysis, which have a philosophical rather than a merely technical base, and which shed light on ‘what is going on’ rather than merely providing a binary decision (it worked/it did not work) derived from an arbitrary criterion for statistical significance and a null hypothesis which is usually known to be false from the start