Lawson criterion for ignition exceeded in an inertial fusion experiment

For more than half a century, researchers around the world have been engaged in attempts to achieve fusion ignition as a proof of principle of various fusion concepts. Following the Lawson criterion, an ignited plasma is one where the fusion heating power is high enough to overcome all the physical processes that cool the fusion plasma, creating a positive thermodynamic feedback loop with rapidly increasing temperature. In inertially confined fusion, ignition is a state where the fusion plasma can begin "burn propagation" into surrounding cold fuel, enabling the possibility of high energy gain. While "scientific breakeven" (i.e., unity target gain) has not yet been achieved (here target gain is 0.72, 1.37 MJ of fusion for 1.92 MJ of laser energy), this Letter reports the first controlled fusion experiment, using laser indirect drive, on the National Ignition Facility to produce capsule gain (here 5.8) and reach ignition by nine different formulations of the Lawson criterion

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

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

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

Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; p = 0.40). There was no significant effect of DMF on any secondary outcome

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

Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; p = 0.40). There was no significant effect of DMF on any secondary outcome

Hidden Markov Model Learning

Hidden Markov Models are introduced as a means to analyze probabilistic\ud systems, with a focus on genetic analysis. Four algorithms are analyzed: the Viterbi algorithm, the Forward algorithm, the Backward algorithm, and the Baum-Welch algorithm. The Viterbi algorithm is used to compute the most probable state path for an emission sequence. The\ud Forward and Backward algorithms are used to calculate the probability\ud of an emission sequence beginning or ending with the observed data,\ud respectively. Finally, the Baum-Welch algorithm uses the Forward and\ud Backward algorithms in order to create a learning algorithm in which the parameters of a Hidden Markov Model are found from a set of training sequences

Construction and characterization of an n-butanol synthetic pathway in Escherichia coli

A diverse array of molecular functions has evolved in biological systems. The ability to reorganize and utilize these remarkable capabilities in order to design pathways for in vivo chemical synthesis requires expanding on foundational biochemical principles in order to better understand the function of entire pathways, thereby allowing for de novo design. Furthermore, in order to integrate these synthetic pathways effectively into organisms such that they are capable of working at the desired high flux, it is necessary to understand the principles affecting pathway flux and pathway interactions with the native metabolism.To this end, we have engineered Escherichia coli to synthesize n-butanol from acetyl-CoA. In design of a high flux de novo pathway, we have demonstrated that using the enzymatic reaction mechanism of the reduction of the enoyl-CoA intermediate as a kinetic control element can drive flux to the final product. This is in constrast to high yield pathways that use a thermodynamic control element to drive the pathway to completion, generally decarboxylation or sequestration of an insoluble product. These methods have the disadvantages of using ATP and limiting the range of target molecules, respectively. Using the enoyl-CoA reduction to drive pathway flux, we have constructed a chimeric pathway capable of producing titers of n-butanol competitive with native fermentative pathways in E. coli (4650 ± 720 mg/L).The enoyl-CoA reductase, tdTer, plays a key role in the production of high titers of n-butanol. We characterized this enzyme structurally and biochemically to examine its potential for use with other substrates. The crystal structure of tdTer was determined to 2.00 Å resolution and shows the enzyme is highly similar to members of the FabV family of enoyl-CoA reductases. Biochemical studies show that similar to other enoyl-CoA (ACP) reductases, the enzyme utilizes an ordered bi-bi reaction mechanism initiated by binding of the NADH redox cofactor. Analysis of the activity and inhibition of the C4, C6, and C12 substrates and products with a variety of binding loop mutants suggests the region is important in discrimination of chain length and points to the major portal as a target for modifying chain length specificity.The introduction of tdTer as the enoyl-CoA reductase was shown to be a key facor in the high yield of n-butanol from our synthetic pathway. In order to study the flux through this step, we implemented a protein scaffold system to colocalize enzymes in the pathway via fusing the enzymes of interest to ligand binding domains. We colocalized tdTer with the enzyme catalyzing the previous step in the biosynthetic pathway and separately with enzyme catalyzing the next step in the pathway. Initial results suggest that the colocalization due to scaffolding can increase n-butanol production, and that the fusion of an affinity tag with the AdhE2 enzyme is capable of increasing specificity of the enzyme. Unfortunately, the deleterious effects of introducing the scaffolding system and the lack of reproducibility in the results prevents the use of the system to effectively probe flux through the n-butanol synthetic pathway.In order to expand the ability of the pathway to probe the metabolism of E. coli, the pathway was modified to draw on the malonyl-CoA pool in addition to acetyl-CoA. To do so, the first enzyme was replaced with NphT7, which condenses one malonyl-CoA and one acetyl-CoA to one acetoacetyl CoA. The introduction of NphT7 creates a significant bottleneck primarily related to malonyl-CoA availability. Increasing the intracellular malonyl-CoA concentration through genetic engineering and heterologous expression was capable of increasing n-butanol production, but not to the levels seen in the acetyl-CoA dependent pathway. We would like to use the modified pathway to identify changes to NphT7 or the host metabolism capable of increasing flux through malonyl-CoA. In order to identify desired mutations to nphT7 and/or the E. coli genome, a strain was developed in which growth rate was correlated with n-butanol production. Use of this strain allowed for the selection of mutated strains with increased n-butanol production; however, low n-butanol yield under selecting conditions and contamination of high yield strains have thus far prevented the idenification of high yield strains. Additional method development allowing for new types of library design is likely necessary in order to identify mutants resulting in high yield malonyl-CoA based pathways