Titan's cold case files - Outstanding questions after Cassini-Huygens

Abstract The entry of the Cassini-Huygens spacecraft into orbit around Saturn in July 2004 marked the start of a golden era in the exploration of Titan, Saturn's giant moon. During the Prime Mission (2004–2008), ground-breaking discoveries were made by the Cassini orbiter including the equatorial dune fields (flyby T3, 2005), northern lakes and seas (T16, 2006), and the large positive and negative ions (T16 & T18, 2006), to name a few. In 2005 the Huygens probe descended through Titan's atmosphere, taking the first close-up pictures of the surface, including large networks of dendritic channels leading to a dried-up seabed, and also obtaining detailed profiles of temperature and gas composition during the atmospheric descent. The discoveries continued through the Equinox Mission (2008–2010) and Solstice Mission (2010–2017) totaling 127 targeted flybys of Titan in all. Now at the end of the mission, we are able to look back on the high-level scientific questions from the start of the mission, and assess the progress that has been made towards answering these. At the same time, new scientific questions regarding Titan have emerged from the discoveries that have been made. In this paper we review a cross-section of important scientific questions that remain partially or completely unanswered, ranging from Titan's deep interior to the exosphere. Our intention is to help formulate the science goals for the next generation of planetary missions to Titan, and to stimulate new experimental, observational and theoretical investigations in the interim

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

eQTL Networks Reveal Complex Genetic Architecture in the Immature Soybean Seed

The complex network of regulatory factors and interactions involved in transcriptional regulation within the seed is not well understood. To evaluate gene expression regulation in the immature seed, we utilized a genetical genomics approach on a soybean [Glycine max (L.) Merr.] recombinant inbred line (RIL) population and produced a genome-wide expression quantitative trait loci (eQTL) dataset. The validity of the dataset was confirmed by mapping the eQTL hotspot for flavonoid biosynthesis-related genes to a region containing repeats of chalcone synthase (CHS) genes known to correspond to the soybean inhibitor locus that regulates seed color. We then identified eQTL for genes with seed-specific expression and discovered striking eQTL hotspots at distinct genomic intervals on chromo-somes (Chr) 20, 7, and 13. The main eQTL hotspot for transcriptional regulation of fatty acid biosyn-thesis genes also coincided with regulation of oleosin genes. Transcriptional upregulation of genesets from eQTL with opposite allelic effects were also found. Gene-eQTL networks were constructed and candidate regulatory genes were identified from these three key loci specific to seed expression and enriched in genes involved in seed oil accumulation. Our data provides new insight into the complex nature of gene networks in the immature soybean seed and the genetic architecture that contributes to seed development

Approximation algorithms for Euclidean group TSP

In the Euclidean group Traveling Salesman Problem (TSP), we are given a set of points P in the plane and a set of m connected regions, each containing at least one point of P. We want to find a tour of minimum length that visits at least one point in each region. This unifies the TSP with Neighborhoods and the Group Steiner Tree problem. We give a (9.1a+1)-approximation algorithm for the case when the regions are disjoint a-fat objects with possibly varying size. This considerably improves the best results known, in this case, for both the group Steiner tree problem and the TSP with Neighborhoods problem. We also give the first O(1)-approximation algorithm for the problem with intersecting regions

Brainstem spreading depolarization and cortical dynamics during fatal seizures in Cacna1a S218L mice

Functional Genomics of Muscle, Nerve and Brain Disorder