Function of hybrid histidine kinases in Arabidopsis flagellin-mediated defence responses

In plants, the first line of microbial recognition relies on the perception of pathogen-associated molecular patterns (PAMPs) allowing plants to detect microorganisms and respond with a set of basal defence responses. The best studied PAMP is flagellin, the main protein component of bacterial flagella. The sensor histidine kinase AHK5 has been shown to play a novel role in mediating flagellin-induced stomatal closure. AHK5 belongs to a family of 9 Arabidopsis hybrid-histidine kinases (HKs). To further investigate the role of such HKs in flagellin-induced signal transduction, physiological responses to the flagellin derived peptide flg22 were examined in available hybrid HK mutant lines. Seedlings of the ethylene insensitive HK ETR1 mutant (etr1-1) showed dramatically reduced flg22 sensitivity as assayed by flg22-mediated seedling growth inhibition. A novel role for the hormone ethylene in flg22-mediated growth inhibition was thus identified. Conversely enhanced sensitivity to low concentrations of flg22 was observed in the AHK2 cytokinin receptor mutant (ahk2-2). However, the absence of flg22-associated growth phenotype in other cytokinin receptor mutants would suggest the role of AHK2 in flg22-mediated seedling growth inhibition may be independent of its role in cytokinin perception. Despite a wild-type sensitivity in aerial plant tissues, distinct flg22-mediated root growth arrest phenotypes were observed in plants defective in the HKs ETR1 and AHK5. Dissection of the mechanisms underlying flg22-mediated root growth inhibition led to the identification of nitric oxide and the ethylene precursor ACC as key secondary messengers. Further characterisation of etr1 mutants showed that, in addition to seedling growth inhibition, ethylene perception is also required for flg22-mediated callose deposition however surprisingly, does not appear to be a requirement for flg22-mediated bacterial immunity. Despite the known requirement for AHK5 in flg22-mediated stomatal closure, flg22-mediated post-invasive bacterial defences were found to be intact in ahk5-1 mutant plants. In summary this study has shown that ethylene perception via the ethylene receptor HK family plays an integral part in flg22-mediated signalling. In addition, organ/tissue specific functions for three of the nine hybrid kinases, AHK2, AHK5 and ETR1 in flg22-mediated signal transduction have been identified

Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK.

BACKGROUND: A safe and efficacious vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), if deployed with high coverage, could contribute to the control of the COVID-19 pandemic. We evaluated the safety and efficacy of the ChAdOx1 nCoV-19 vaccine in a pooled interim analysis of four trials. METHODS: This analysis includes data from four ongoing blinded, randomised, controlled trials done across the UK, Brazil, and South Africa. Participants aged 18 years and older were randomly assigned (1:1) to ChAdOx1 nCoV-19 vaccine or control (meningococcal group A, C, W, and Y conjugate vaccine or saline). Participants in the ChAdOx1 nCoV-19 group received two doses containing 5 × 1010 viral particles (standard dose; SD/SD cohort); a subset in the UK trial received a half dose as their first dose (low dose) and a standard dose as their second dose (LD/SD cohort). The primary efficacy analysis included symptomatic COVID-19 in seronegative participants with a nucleic acid amplification test-positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to treatment received, with data cutoff on Nov 4, 2020. Vaccine efficacy was calculated as 1 - relative risk derived from a robust Poisson regression model adjusted for age. Studies are registered at ISRCTN89951424 and ClinicalTrials.gov, NCT04324606, NCT04400838, and NCT04444674. FINDINGS: Between April 23 and Nov 4, 2020, 23 848 participants were enrolled and 11 636 participants (7548 in the UK, 4088 in Brazil) were included in the interim primary efficacy analysis. In participants who received two standard doses, vaccine efficacy was 62·1% (95% CI 41·0-75·7; 27 [0·6%] of 4440 in the ChAdOx1 nCoV-19 group vs71 [1·6%] of 4455 in the control group) and in participants who received a low dose followed by a standard dose, efficacy was 90·0% (67·4-97·0; three [0·2%] of 1367 vs 30 [2·2%] of 1374; pinteraction=0·010). Overall vaccine efficacy across both groups was 70·4% (95·8% CI 54·8-80·6; 30 [0·5%] of 5807 vs 101 [1·7%] of 5829). From 21 days after the first dose, there were ten cases hospitalised for COVID-19, all in the control arm; two were classified as severe COVID-19, including one death. There were 74 341 person-months of safety follow-up (median 3·4 months, IQR 1·3-4·8): 175 severe adverse events occurred in 168 participants, 84 events in the ChAdOx1 nCoV-19 group and 91 in the control group. Three events were classified as possibly related to a vaccine: one in the ChAdOx1 nCoV-19 group, one in the control group, and one in a participant who remains masked to group allocation. INTERPRETATION: ChAdOx1 nCoV-19 has an acceptable safety profile and has been found to be efficacious against symptomatic COVID-19 in this interim analysis of ongoing clinical trials. FUNDING: UK Research and Innovation, National Institutes for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, Bill & Melinda Gates Foundation, Lemann Foundation, Rede D'Or, Brava and Telles Foundation, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and AstraZeneca

Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK

Background A safe and efficacious vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), if deployed with high coverage, could contribute to the control of the COVID-19 pandemic. We evaluated the safety and efficacy of the ChAdOx1 nCoV-19 vaccine in a pooled interim analysis of four trials. Methods This analysis includes data from four ongoing blinded, randomised, controlled trials done across the UK, Brazil, and South Africa. Participants aged 18 years and older were randomly assigned (1:1) to ChAdOx1 nCoV-19 vaccine or control (meningococcal group A, C, W, and Y conjugate vaccine or saline). Participants in the ChAdOx1 nCoV-19 group received two doses containing 5 × 1010 viral particles (standard dose; SD/SD cohort); a subset in the UK trial received a half dose as their first dose (low dose) and a standard dose as their second dose (LD/SD cohort). The primary efficacy analysis included symptomatic COVID-19 in seronegative participants with a nucleic acid amplification test-positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to treatment received, with data cutoff on Nov 4, 2020. Vaccine efficacy was calculated as 1 - relative risk derived from a robust Poisson regression model adjusted for age. Studies are registered at ISRCTN89951424 and ClinicalTrials.gov, NCT04324606, NCT04400838, and NCT04444674. Findings Between April 23 and Nov 4, 2020, 23 848 participants were enrolled and 11 636 participants (7548 in the UK, 4088 in Brazil) were included in the interim primary efficacy analysis. In participants who received two standard doses, vaccine efficacy was 62·1% (95% CI 41·0–75·7; 27 [0·6%] of 4440 in the ChAdOx1 nCoV-19 group vs71 [1·6%] of 4455 in the control group) and in participants who received a low dose followed by a standard dose, efficacy was 90·0% (67·4–97·0; three [0·2%] of 1367 vs 30 [2·2%] of 1374; pinteraction=0·010). Overall vaccine efficacy across both groups was 70·4% (95·8% CI 54·8–80·6; 30 [0·5%] of 5807 vs 101 [1·7%] of 5829). From 21 days after the first dose, there were ten cases hospitalised for COVID-19, all in the control arm; two were classified as severe COVID-19, including one death. There were 74 341 person-months of safety follow-up (median 3·4 months, IQR 1·3–4·8): 175 severe adverse events occurred in 168 participants, 84 events in the ChAdOx1 nCoV-19 group and 91 in the control group. Three events were classified as possibly related to a vaccine: one in the ChAdOx1 nCoV-19 group, one in the control group, and one in a participant who remains masked to group allocation. Interpretation ChAdOx1 nCoV-19 has an acceptable safety profile and has been found to be efficacious against symptomatic COVID-19 in this interim analysis of ongoing clinical trials

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Function of hybrid histidine kinases in Arabidopsis flagellin-mediated defence responses

In plants, the first line of microbial recognition relies on the perception of pathogen-associated molecular patterns (PAMPs) allowing plants to detect microorganisms and respond with a set of basal defence responses. The best studied PAMP is flagellin, the main protein component of bacterial flagella. The sensor histidine kinase AHK5 has been shown to play a novel role in mediating flagellin-induced stomatal closure. AHK5 belongs to a family of 9 Arabidopsis hybrid-histidine kinases (HKs). To further investigate the role of such HKs in flagellin-induced signal transduction, physiological responses to the flagellin derived peptide flg22 were examined in available hybrid HK mutant lines. Seedlings of the ethylene insensitive HK ETR1 mutant (etr1-1) showed dramatically reduced flg22 sensitivity as assayed by flg22-mediated seedling growth inhibition. A novel role for the hormone ethylene in flg22-mediated growth inhibition was thus identified. Conversely enhanced sensitivity to low concentrations of flg22 was observed in the AHK2 cytokinin receptor mutant (ahk2-2). However, the absence of flg22-associated growth phenotype in other cytokinin receptor mutants would suggest the role of AHK2 in flg22-mediated seedling growth inhibition may be independent of its role in cytokinin perception. Despite a wild-type sensitivity in aerial plant tissues, distinct flg22-mediated root growth arrest phenotypes were observed in plants defective in the HKs ETR1 and AHK5. Dissection of the mechanisms underlying flg22-mediated root growth inhibition led to the identification of nitric oxide and the ethylene precursor ACC as key secondary messengers. Further characterisation of etr1 mutants showed that, in addition to seedling growth inhibition, ethylene perception is also required for flg22-mediated callose deposition however surprisingly, does not appear to be a requirement for flg22-mediated bacterial immunity. Despite the known requirement for AHK5 in flg22-mediated stomatal closure, flg22-mediated post-invasive bacterial defences were found to be intact in ahk5-1 mutant plants. In summary this study has shown that ethylene perception via the ethylene receptor HK family plays an integral part in flg22-mediated signalling. In addition, organ/tissue specific functions for three of the nine hybrid kinases, AHK2, AHK5 and ETR1 in flg22-mediated signal transduction have been identified.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Function of hybrid histidine kinases in Arabidopsis flagellin-mediated defence responses

In plants, the first line of microbial recognition relies on the perception of pathogen-associated molecular patterns (PAMPs) allowing plants to detect microorganisms and respond with a set of basal defence responses. The best studied PAMP is flagellin, the main protein component of bacterial flagella. The sensor histidine kinase AHK5 has been shown to play a novel role in mediating flagellin-induced stomatal closure. AHK5 belongs to a family of 9 Arabidopsis hybrid-histidine kinases (HKs). To further investigate the role of such HKs in flagellin-induced signal transduction, physiological responses to the flagellin derived peptide flg22 were examined in available hybrid HK mutant lines. Seedlings of the ethylene insensitive HK ETR1 mutant (etr1-1) showed dramatically reduced flg22 sensitivity as assayed by flg22-mediated seedling growth inhibition. A novel role for the hormone ethylene in flg22-mediated growth inhibition was thus identified. Conversely enhanced sensitivity to low concentrations of flg22 was observed in the AHK2 cytokinin receptor mutant (ahk2-2). However, the absence of flg22-associated growth phenotype in other cytokinin receptor mutants would suggest the role of AHK2 in flg22-mediated seedling growth inhibition may be independent of its role in cytokinin perception. Despite a wild-type sensitivity in aerial plant tissues, distinct flg22-mediated root growth arrest phenotypes were observed in plants defective in the HKs ETR1 and AHK5. Dissection of the mechanisms underlying flg22-mediated root growth inhibition led to the identification of nitric oxide and the ethylene precursor ACC as key secondary messengers. Further characterisation of etr1 mutants showed that, in addition to seedling growth inhibition, ethylene perception is also required for flg22-mediated callose deposition however surprisingly, does not appear to be a requirement for flg22-mediated bacterial immunity. Despite the known requirement for AHK5 in flg22-mediated stomatal closure, flg22-mediated post-invasive bacterial defences were found to be intact in ahk5-1 mutant plants. In summary this study has shown that ethylene perception via the ethylene receptor HK family plays an integral part in flg22-mediated signalling. In addition, organ/tissue specific functions for three of the nine hybrid kinases, AHK2, AHK5 and ETR1 in flg22-mediated signal transduction have been identified.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Transforming knowledge systems for life on Earth : Visions of future systems and how to get there

Formalised knowledge systems, including universities and research institutes, are important for contemporary societies. They are, however, also arguably failing humanity when their impact is measured against the level of progress being made in stimulating the societal changes needed to address challenges like climate change. In this research we used a novel futures-oriented and participatory approach that asked what future envisioned knowledge systems might need to look like and how we might get there. Findings suggest that envisioned future systems will need to be much more collaborative, open, diverse, egalitarian, and able to work with values and systemic issues. They will also need to go beyond producing knowledge about our world to generating wisdom about how to act within it. To get to envisioned systems we will need to rapidly scale methodological innovations, connect innovators, and creatively accelerate learning about working with intractable challenges. We will also need to create new funding schemes, a global knowledge commons, and challenge deeply held assumptions. To genuinely be a creative force in supporting longevity of human and non-human life on our planet, the shift in knowledge systems will probably need to be at the scale of the enlightenment and speed of the scientific and technological revolution accompanying the second World War. This will require bold and strategic action from governments, scientists, civic society and sustained transformational intent.Peer reviewe

Transforming knowledge systems for life on Earth: Visions of future systems and how to get there

Formalised knowledge systems, including universities and research institutes, are important for contemporary societies. They are, however, also arguably failing humanity when their impact is measured against the level of progress being made in stimulating the societal changes needed to address challenges like climate change. In this research we used a novel futures-oriented and participatory approach that asked what future envisioned knowledge systems might need to look like and how we might get there. Findings suggest that envisioned future systems will need to be much more collaborative, open, diverse, egalitarian, and able to work with values and systemic issues. They will also need to go beyond producing knowledge about our world to generating wisdom about how to act within it. To get to envisioned systems we will need to rapidly scale methodological innovations, connect innovators, and creatively accelerate learning about working with intractable challenges. We will also need to create new funding schemes, a global knowledge commons, and challenge deeply held assumptions. To genuinely be a creative force in supporting longevity of human and non-human life on our planet, the shift in knowledge systems will probably need to be at the scale of the enlightenment and speed of the scientific and technological revolution accompanying the second World War. This will require bold and strategic action from governments, scientists, civic society and sustained transformational intent

Empagliflozin in Patients with Chronic Kidney Disease

Background The effects of empagliflozin in patients with chronic kidney disease who are at risk for disease progression are not well understood. The EMPA-KIDNEY trial was designed to assess the effects of treatment with empagliflozin in a broad range of such patients. Methods We enrolled patients with chronic kidney disease who had an estimated glomerular filtration rate (eGFR) of at least 20 but less than 45 ml per minute per 1.73 m(2) of body-surface area, or who had an eGFR of at least 45 but less than 90 ml per minute per 1.73 m(2) with a urinary albumin-to-creatinine ratio (with albumin measured in milligrams and creatinine measured in grams) of at least 200. Patients were randomly assigned to receive empagliflozin (10 mg once daily) or matching placebo. The primary outcome was a composite of progression of kidney disease (defined as end-stage kidney disease, a sustained decrease in eGFR to < 10 ml per minute per 1.73 m(2), a sustained decrease in eGFR of & GE;40% from baseline, or death from renal causes) or death from cardiovascular causes. Results A total of 6609 patients underwent randomization. During a median of 2.0 years of follow-up, progression of kidney disease or death from cardiovascular causes occurred in 432 of 3304 patients (13.1%) in the empagliflozin group and in 558 of 3305 patients (16.9%) in the placebo group (hazard ratio, 0.72; 95% confidence interval [CI], 0.64 to 0.82; P < 0.001). Results were consistent among patients with or without diabetes and across subgroups defined according to eGFR ranges. The rate of hospitalization from any cause was lower in the empagliflozin group than in the placebo group (hazard ratio, 0.86; 95% CI, 0.78 to 0.95; P=0.003), but there were no significant between-group differences with respect to the composite outcome of hospitalization for heart failure or death from cardiovascular causes (which occurred in 4.0% in the empagliflozin group and 4.6% in the placebo group) or death from any cause (in 4.5% and 5.1%, respectively). The rates of serious adverse events were similar in the two groups. Conclusions Among a wide range of patients with chronic kidney disease who were at risk for disease progression, empagliflozin therapy led to a lower risk of progression of kidney disease or death from cardiovascular causes than placebo