Isopentenol Utilization Pathway for the Production of Linalool in Escherichia coli Using an Improved Bacterial Linalool/Nerolidol Synthase

From Wiley via Jisc Publications RouterHistory: received 2021-03-10, rev-recd 2021-05-02, pub-electronic 2021-05-25Article version: VoRPublication status: PublishedFunder: Future Biomanufacturing Research Hub; Grant(s): EP/S01778X/1Funder: Engineering and Physical Sciences Research Council; Id: http://dx.doi.org/10.13039/501100000266Funder: Biotechnology and Biological Sciences Research Council; Id: http://dx.doi.org/10.13039/501100000268Funder: Office of Naval Research Global; Id: http://dx.doi.org/10.13039/100007297Abstract: Linalool is a monoterpenoid used as a fragrance ingredient, and is a promising source for alternative fuels. Synthetic biology offers attractive alternative production methods compared to extraction from natural sources and chemical synthesis. Linalool/nerolidol synthase (bLinS) from Streptomyces clavuligerus is a bifunctional enzyme, producing linalool as well as the sesquiterpenoid nerolidol when expressed in engineered Escherichia coli harbouring a precursor terpenoid pathway such as the mevalonate (MVA) pathway. Here we identified two residues important for substrate selection by bLinS, L72 and V214, where the introduction of bulkier residues results in variants with reduced nerolidol formation. Terpenoid production using canonical precursor pathways is usually limited by numerous and highly regulated enzymatic steps. Here we compared the canonical MVA pathway to the non‐canonical isopentenol utilization (IU) pathway to produce linalool using the optimised bLinS variant. The IU pathway uses isoprenol and prenol to produce linalool in only five steps. Adjusting substrate, plasmid system, inducer concentration, and cell strain directs the flux towards monoterpenoids. Our integrated approach, combining enzyme engineering with flux control using the artificial IU pathway, resulted in high purity production of the commercially attractive monoterpenoid linalool, and will guide future efforts towards efficient optimisation of terpenoid production in engineered microbes

Adipokines: Linking metabolic syndrome, the immune system, and arthritic diseases

Metabolic syndrome (MetS) represents a cluster of metabolic and cardiovascular complications, including obesity and visceral adiposity, insulin resistance, dyslipidemia, hyperglycemia and hypertension, which directly increase the risk of cardiovascular diseases (CVD) and diabetes mellitus type 2 (DM2). Patients with arthritic diseases, such as rheumatoid arthritis and osteoarthritis, have a higher incidence of CVD. Although recent advances in the treatment of arthritic diseases, the incidence of CVD remains elevated, and MetS has been identified as a possible link between CVD and arthritic diseases. Chronic low-grade inflammation associated with obesity has been established as a significant contributing factor to the increased prevalence of MetS. Adipokines, which play important physiological roles in metabolic activities contributing to the pathogenesis of MetS, are also involved in the regulation of autoimmune and/or inflammatory processes associated with arthritic diseases. Therefore, MetS and dysregulated secretion of pro-inflammatory adipokines have been recognized as a molecular link between CVD and arthritis diseases. In the present paper, we review recent evidence supporting the role played by adipokines, in particular leptin, adiponectin, and lipocalin-2, in the modulation of the immune system, MetS and arthritic diseases. The underlying cellular and molecular mechanisms are discussed, as well as potential new therapeutic strategies.Acknowledgments: OG and FL are Staff Personnel of Xunta de Galicia (Servizo Galego de Saude, SERGAS) through a research-staff stabilization contract (ISCIII/SERGAS). VF is a “Sara Borrell” Researcher funded by ISCIII and FEDER (CD16/00111). RG is a “Miguel Servet” Researcher funded by Instituto de Salud Carlos III (ISCIII) and FEDER. CRF is a pre-doctoral research scholar funded by ISCIII and FEDER (Exp.18/00188). OG, MAGG, and RG are members of RETICS Programme, RD16/0012/0014 (RIER: Red de Investigación en Inflamación y Enfermedades Reumáticas) via Instituto de Salud Carlos III (ISCIII) and FEDER. FL is a member of CIBERCV (Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares). The work of OG and JP (PI17/00409), RG (PI16/01870 and CP15/00007) and FL (PI15/00681 PI18/00821 and CB16/11/00226) were funded by Instituto de Salud Carlos III and FEDER. OG is a beneficiary of a project funded by Research Executive Agency of the European Union in the framework of MSCA-RISE Action of the H2020 Programme (Project number 734899). RG is beneficiary of a project funded by Mutua Madrileña 2018. AM wishes to acknowledge financial support from the European Structural and Social Funds through the Research Council of Lithuania (Lietuvos Mokslo Taryba) according to the activity ‘Improvement of researchers’ qualification by implementing world-class R&D projects’ of Measure No. 09.3.3-LMT-K-712 (grant application code: 09.3.3-LMT-K-712-01-0157, agreement No. DOTSUT-215) and the new funding programme: Attracting Foreign Researchers for Research Implementation (2018–2022). The funders had no role in study design, data collection, and analysis, decision to publish, or preparation of the manuscript

Reconstructing the Deep Population History of Central and South America

We report genome-wide ancient DNA from 49 individuals forming four parallel time transects in Belize, Brazil, the Central Andes, and the Southern Cone, each dating to at least 9,000 years ago. The common ancestral population radiated rapidly from just one of the two early branches that contributed to Native Americans today. We document two previously unappreciated streams of gene flow between North and South America. One affected the Central Andes by 4,200 years ago, while the other explains an affinity between the oldest North American genome associated with the Clovis culture and the oldest Central and South Americans from Chile, Brazil, and Belize. However, this was not the primary source for later South Americans, as the other ancient individuals derive from lineages without specific affinity to the Clovis-associated genome, suggesting a population replacement that began at least 9,000 years ago and was followed by substantial population continuity in multiple regions

Study of ordered hadron chains with the ATLAS detector

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A search for resonances decaying into a Higgs boson and a new particle X in the XH→qqbb final state with the ATLAS detector

A search for heavy resonances decaying into a Higgs boson ($H$) and a new particle ($X$) is reported, utilizing 36.1 fb$^{-1}$ of proton-proton collision data at $\sqrt{s} =$ 13 TeV collected during 2015 and 2016 with the ATLAS detector at the CERN Large Hadron Collider. The particle $X$ is assumed to decay to a pair of light quarks, and the fully hadronic final state $XH \rightarrow q\bar q'b\bar b$ is analysed. The search considers the regime of high $XH$ resonance masses, where the $X$ and $H$ bosons are both highly Lorentz-boosted and are each reconstructed using a single jet with large radius parameter. A two-dimensional phase space of $XH$ mass versus $X$ mass is scanned for evidence of a signal, over a range of $XH$ resonance mass values between 1 TeV and 4 TeV, and for $X$ particles with masses from 50 GeV to 1000 GeV. All search results are consistent with the expectations for the background due to Standard Model processes, and 95% CL upper limits are set, as a function of $XH$ and $X$ masses, on the production cross-section of the $XH\rightarrow q\bar q'b\bar b$ resonance

Study of the material of the ATLAS inner detector for Run 2 of the LHC

Instituto de Física La Plat

COVID-19 symptoms at hospital admission vary with age and sex: results from the ISARIC prospective multinational observational study

Background: The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms. Methods: International, prospective observational study of 60 109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms. Results: ‘Typical’ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69%; at least one 95%). They were reported less frequently in children (≤ 18 years: 69, 48, 23; 85%), older adults (≥ 70 years: 61, 62, 65; 90%), and women (66, 66, 64; 90%; vs. men 71, 70, 67; 93%, each P < 0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country. Interpretation: This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men

Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction, GALACTIC‐HF: baseline characteristics and comparison with contemporary clinical trials

Aims: The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC‐HF) trial. Here we describe the baseline characteristics of participants in GALACTIC‐HF and how these compare with other contemporary trials. Methods and Results: Adults with established HFrEF, New York Heart Association functional class (NYHA) ≥ II, EF ≤35%, elevated natriuretic peptides and either current hospitalization for HF or history of hospitalization/ emergency department visit for HF within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic‐guided dosing: 25, 37.5 or 50 mg bid). 8256 patients [male (79%), non‐white (22%), mean age 65 years] were enrolled with a mean EF 27%, ischemic etiology in 54%, NYHA II 53% and III/IV 47%, and median NT‐proBNP 1971 pg/mL. HF therapies at baseline were among the most effectively employed in contemporary HF trials. GALACTIC‐HF randomized patients representative of recent HF registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure < 100 mmHg (n = 1127), estimated glomerular filtration rate < 30 mL/min/1.73 m2 (n = 528), and treated with sacubitril‐valsartan at baseline (n = 1594). Conclusions: GALACTIC‐HF enrolled a well‐treated, high‐risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation