Microbial engineering of new streptomyces sp. from extreme environments for novel antibiotics and anticancer drugs

Today there is a tremendous need for new antibiotics and novel cytotoxic compounds against cancer cells to develop efficient alternative treatment to chemotherapy. We have searched for highly active Streptomyces strains in the driest desert in the world, the Atacama desert in northern Chile. We have identified several new strains and found many novel antibiotics and anticancer agents (“Chaxamycins”, “Chaxalactins” and “Atacamycins”) from Streptomyces C34 and C38. A genome scale model of the metabolism of Streptomyces leeuwenhoekii C34 has been developed from its genome sequence. The model, iVR1007, has 1726 reactions including 239 for transport, reactions for secondary metabolite biosynthesis, 1463 metabolites and 1007 genes. The model was validated with experimental data of growth in 89, 54 and 23 sole carbon, nitrogen and phosphorous sources, respectively, and showed a high level of accuracy (82.5 %). We have included reactions for desferrioxamines, ectoine, Chaxamycins, Chaxalactins and for the hybrid polyketides/non-ribosomal peptide synthesized by the halogenase cluster. A detailed Metabolic Flux Balance Analysis was carried out in order to study the metabolic pathways of Chaxalactins, Chaxamycins and the product of the halogenase cluster, by recognizing overexpression targets and useful knock-out sites to increase production of these secondary metabolites. Alternatively we have identified the gene cluster in S. leeuwenhoekii C34 responsible for the biosynthesis of the Chaxamycins and Chaxalactins and have cloned the whole gene cluster in a much more efficient strain of Streptomyces, namely S. coelicolor A3 whose heterologous expression of gene clusters from other Streptomyces strains has been successfully tested. Our recent results concerning these two alternative strategies for identification and overproduction of these important secondary metabolites will be presented and discussed in this presentation

Size Doesn't Matter: Towards a More Inclusive Philosophy of Biology

notes: As the primary author, O’Malley drafted the paper, and gathered and analysed data (scientific papers and talks). Conceptual analysis was conducted by both authors.publication-status: Publishedtypes: ArticlePhilosophers of biology, along with everyone else, generally perceive life to fall into two broad categories, the microbes and macrobes, and then pay most of their attention to the latter. ‘Macrobe’ is the word we propose for larger life forms, and we use it as part of an argument for microbial equality. We suggest that taking more notice of microbes – the dominant life form on the planet, both now and throughout evolutionary history – will transform some of the philosophy of biology’s standard ideas on ontology, evolution, taxonomy and biodiversity. We set out a number of recent developments in microbiology – including biofilm formation, chemotaxis, quorum sensing and gene transfer – that highlight microbial capacities for cooperation and communication and break down conventional thinking that microbes are solely or primarily single-celled organisms. These insights also bring new perspectives to the levels of selection debate, as well as to discussions of the evolution and nature of multicellularity, and to neo-Darwinian understandings of evolutionary mechanisms. We show how these revisions lead to further complications for microbial classification and the philosophies of systematics and biodiversity. Incorporating microbial insights into the philosophy of biology will challenge many of its assumptions, but also give greater scope and depth to its investigations

Geographical and temporal distribution of SARS-CoV-2 clades in the WHO European Region, January to June 2020

We show the distribution of SARS-CoV-2 genetic clades over time and between countries and outline potential genomic surveillance objectives. We applied three available genomic nomenclature systems for SARS-CoV-2 to all sequence data from the WHO European Region available during the COVID-19 pandemic until 10 July 2020. We highlight the importance of real-time sequencing and data dissemination in a pandemic situation. We provide a comparison of the nomenclatures and lay a foundation for future European genomic surveillance of SARS-CoV-2.Peer reviewe

Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Background: In this study, we aimed to evaluate the effects of tocilizumab in adult patients admitted to hospital with COVID-19 with both hypoxia and systemic inflammation. Methods: This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. Those trial participants with hypoxia (oxygen saturation <92% on air or requiring oxygen therapy) and evidence of systemic inflammation (C-reactive protein ≥75 mg/L) were eligible for random assignment in a 1:1 ratio to usual standard of care alone versus usual standard of care plus tocilizumab at a dose of 400 mg–800 mg (depending on weight) given intravenously. A second dose could be given 12–24 h later if the patient's condition had not improved. The primary outcome was 28-day mortality, assessed in the intention-to-treat population. The trial is registered with ISRCTN (50189673) and ClinicalTrials.gov (NCT04381936). Findings: Between April 23, 2020, and Jan 24, 2021, 4116 adults of 21 550 patients enrolled into the RECOVERY trial were included in the assessment of tocilizumab, including 3385 (82%) patients receiving systemic corticosteroids. Overall, 621 (31%) of the 2022 patients allocated tocilizumab and 729 (35%) of the 2094 patients allocated to usual care died within 28 days (rate ratio 0·85; 95% CI 0·76–0·94; p=0·0028). Consistent results were seen in all prespecified subgroups of patients, including those receiving systemic corticosteroids. Patients allocated to tocilizumab were more likely to be discharged from hospital within 28 days (57% vs 50%; rate ratio 1·22; 1·12–1·33; p<0·0001). Among those not receiving invasive mechanical ventilation at baseline, patients allocated tocilizumab were less likely to reach the composite endpoint of invasive mechanical ventilation or death (35% vs 42%; risk ratio 0·84; 95% CI 0·77–0·92; p<0·0001). Interpretation: In hospitalised COVID-19 patients with hypoxia and systemic inflammation, tocilizumab improved survival and other clinical outcomes. These benefits were seen regardless of the amount of respiratory support and were additional to the benefits of systemic corticosteroids. Funding: UK Research and Innovation (Medical Research Council) and National Institute of Health Research

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

Background: Many patients with COVID-19 have been treated with plasma containing anti-SARS-CoV-2 antibodies. We aimed to evaluate the safety and efficacy of convalescent plasma therapy in patients admitted to hospital with COVID-19. Methods: This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]) is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. The trial is underway at 177 NHS hospitals from across the UK. Eligible and consenting patients were randomly assigned (1:1) to receive either usual care alone (usual care group) or usual care plus high-titre convalescent plasma (convalescent plasma group). The primary outcome was 28-day mortality, analysed on an intention-to-treat basis. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936. Findings: Between May 28, 2020, and Jan 15, 2021, 11558 (71%) of 16287 patients enrolled in RECOVERY were eligible to receive convalescent plasma and were assigned to either the convalescent plasma group or the usual care group. There was no significant difference in 28-day mortality between the two groups: 1399 (24%) of 5795 patients in the convalescent plasma group and 1408 (24%) of 5763 patients in the usual care group died within 28 days (rate ratio 1·00, 95% CI 0·93–1·07; p=0·95). The 28-day mortality rate ratio was similar in all prespecified subgroups of patients, including in those patients without detectable SARS-CoV-2 antibodies at randomisation. Allocation to convalescent plasma had no significant effect on the proportion of patients discharged from hospital within 28 days (3832 [66%] patients in the convalescent plasma group vs 3822 [66%] patients in the usual care group; rate ratio 0·99, 95% CI 0·94–1·03; p=0·57). Among those not on invasive mechanical ventilation at randomisation, there was no significant difference in the proportion of patients meeting the composite endpoint of progression to invasive mechanical ventilation or death (1568 [29%] of 5493 patients in the convalescent plasma group vs 1568 [29%] of 5448 patients in the usual care group; rate ratio 0·99, 95% CI 0·93–1·05; p=0·79). Interpretation: In patients hospitalised with COVID-19, high-titre convalescent plasma did not improve survival or other prespecified clinical outcomes. Funding: UK Research and Innovation (Medical Research Council) and National Institute of Health Research

Experimental Investigation of Existing Hollowcore Seating Connection Seismic Behaviour Pre and Post Retrofit Intervention,

In the recent past a number of issues regarding the seismic performance of typical existing hollowcore floor systems have been raised. The most concerning of these is the vulnerability to loss of vertical support of the floor system at the end floor to seating beam connection. This vulnerability arises due to incompatibilities between the floor system and intrinsic deformations of the neighbouring seismic frames. In a previous contribution by the authors (Jensen et al 2006), a conceptual retrofit strategy for existing hollowcore seating connections was proposed. This paper provides an experimental validation of that strategy through quasi-static cyclic testing of alternative seating connection configurations, adopting varying seating lengths. In general, unfavourable performance was exhibited by the existing seating connections, resulting in loss of vertical support of the hollowcore unit. In contrast, when additional seating and selective weakening retrofit approaches were implemented, a higher level of seismic performance leading to collapse prevention was achieved. In conclusion, issues and uncertainties associated with the evaluation of the likely failure mechanism, as well as the definition of an appropriate retrofit intervention are discussed

Conceptual retrofit strategy for existing hollowcore seating connections

Previous research regarding the seismic performance of existing precast hollowcore floor and ductile lateral frame systems has highlighted several behavioural uncertainties. In particular poor seismic performance due to deformation incompatibilities between the floor diaphragm and frame seismic resisting system have become apparent. Significant rotation and displacement demand on the floor systems due to frame beam elongation, seating beam rotation, and longitudinal perimeter vertical displacement have been identified as the main sources of undesirable damage. As a result the structural integrity at hollowcore seating and perimeter connection interfaces can be jeopardised, potentially leading to a partial or even complete floor collapse. In this paper an overview of expected compatibility issues is given while providing suggestions for conceptual low-invasive retrofit strategies. Particular focus will be given to the experimental investigation on the vulnerability of and suggested retrofit solutions for hollow core-seating connections. The Quasi-static experimental testing procedure focusing on a series of as-built and retrofitted specimens, reproducing a hollowcore-toseating- beam connection with traditionally adopted details will be presented. Both seating rotation due to the imposed lateral drift and beam elongation effects are simulated in the applied testing set-up. Simplified analysis and modelling aspects regarding the connection behaviour are discussed; expected damage and performance criteria associated with the alternative existing or retrofit solution are also tentatively indicated