The optical spectrum of a large isolated polycyclic aromatic hydrocarbon: hexa-peri-hexabenzocoronene, C42H18

The first optical spectrum of an isolated polycyclic aromatic hydrocarbon large enough to survive the photophysical conditions of the interstellar medium is reported. Vibronic bands of the first electronic transition of the all benzenoid polycyclic aromatic hydrocarbon hexa-peri-hexabenzocoronene were observed in the 4080-4530 Angstrom range by resonant 2-color 2-photon ionization spectroscopy. The strongest feature at 4264 Angstrom is estimated to have an oscillator strength of f=1.4x10^-3, placing an upper limit on the interstellar abundance of this polycyclic aromatic hydrocarbon at 4x10^12 cm^-2, accounting for a maximum of ~0.02% of interstellar carbon. This study opens up the possibility to rigorously test neutral polycyclic aromatic hydrocarbons as carriers of the diffuse interstellar bands in the near future.Comment: 9 pages, 1 figure. Fixed a typo on the frequency of the 'b' ban

The Early Royal Society and Visual Culture

Recent studies have fruitfully examined the intersection between early modern science and visual culture by elucidating the functions of images in shaping and disseminating scientific knowledge. Given its rich archival sources, it is possible to extend this line of research in the case of the Royal Society to an examination of attitudes towards images as artefacts –manufactured objects worth commissioning, collecting and studying. Drawing on existing scholarship and material from the Royal Society Archives, I discuss Fellows’ interests in prints, drawings, varnishes, colorants, images made out of unusual materials, and methods of identifying the painter from a painting. Knowledge of production processes of images was important to members of the Royal Society, not only as connoisseurs and collectors, but also as those interested in a Baconian mastery of material processes, including a “history of trades”. Their antiquarian interests led to discussion of painters’ styles, and they gradually developed a visual memorial to an institution through portraits and other visual records.AH/M001938/1 (AHRC

Impact of primary kidney disease on the effects of empagliflozin in patients with chronic kidney disease: secondary analyses of the EMPA-KIDNEY trial

Background: The EMPA KIDNEY trial showed that empagliflozin reduced the risk of the primary composite outcome of kidney disease progression or cardiovascular death in patients with chronic kidney disease mainly through slowing progression. We aimed to assess how effects of empagliflozin might differ by primary kidney disease across its broad population. Methods: EMPA-KIDNEY, a randomised, controlled, phase 3 trial, was conducted at 241 centres in eight countries (Canada, China, Germany, Italy, Japan, Malaysia, the UK, and the USA). Patients were eligible if their estimated glomerular filtration rate (eGFR) was 20 to less than 45 mL/min per 1·73 m2, or 45 to less than 90 mL/min per 1·73 m2 with a urinary albumin-to-creatinine ratio (uACR) of 200 mg/g or higher at screening. They were randomly assigned (1:1) to 10 mg oral empagliflozin once daily or matching placebo. Effects on kidney disease progression (defined as a sustained ≥40% eGFR decline from randomisation, end-stage kidney disease, a sustained eGFR below 10 mL/min per 1·73 m2, or death from kidney failure) were assessed using prespecified Cox models, and eGFR slope analyses used shared parameter models. Subgroup comparisons were performed by including relevant interaction terms in models. EMPA-KIDNEY is registered with ClinicalTrials.gov, NCT03594110. Findings: Between May 15, 2019, and April 16, 2021, 6609 participants were randomly assigned and followed up for a median of 2·0 years (IQR 1·5–2·4). Prespecified subgroupings by primary kidney disease included 2057 (31·1%) participants with diabetic kidney disease, 1669 (25·3%) with glomerular disease, 1445 (21·9%) with hypertensive or renovascular disease, and 1438 (21·8%) with other or unknown causes. Kidney disease progression occurred in 384 (11·6%) of 3304 patients in the empagliflozin group and 504 (15·2%) of 3305 patients in the placebo group (hazard ratio 0·71 [95% CI 0·62–0·81]), with no evidence that the relative effect size varied significantly by primary kidney disease (pheterogeneity=0·62). The between-group difference in chronic eGFR slopes (ie, from 2 months to final follow-up) was 1·37 mL/min per 1·73 m2 per year (95% CI 1·16–1·59), representing a 50% (42–58) reduction in the rate of chronic eGFR decline. This relative effect of empagliflozin on chronic eGFR slope was similar in analyses by different primary kidney diseases, including in explorations by type of glomerular disease and diabetes (p values for heterogeneity all >0·1). Interpretation: In a broad range of patients with chronic kidney disease at risk of progression, including a wide range of non-diabetic causes of chronic kidney disease, empagliflozin reduced risk of kidney disease progression. Relative effect sizes were broadly similar irrespective of the cause of primary kidney disease, suggesting that SGLT2 inhibitors should be part of a standard of care to minimise risk of kidney failure in chronic kidney disease. Funding: Boehringer Ingelheim, Eli Lilly, and UK Medical Research Council

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figure

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Integration of shallow gradients of Shh and Netrin-1 guides commissural axons.

During nervous system development, gradients of Sonic Hedgehog (Shh) and Netrin-1 attract growth cones of commissural axons toward the floor plate of the embryonic spinal cord. Mice defective for either Shh or Netrin-1 signaling have commissural axon guidance defects, suggesting that both Shh and Netrin-1 are required for correct axon guidance. However, how Shh and Netrin-1 collaborate to guide axons is not known. We first quantified the steepness of the Shh gradient in the spinal cord and found that it is mostly very shallow. We then developed an in vitro microfluidic guidance assay to simulate these shallow gradients. We found that axons of dissociated commissural neurons respond to steep but not shallow gradients of Shh or Netrin-1. However, when we presented axons with combined Shh and Netrin-1 gradients, they had heightened sensitivity to the guidance cues, turning in response to shallower gradients that were unable to guide axons when only one cue was present. Furthermore, these shallow gradients polarized growth cone Src-family kinase (SFK) activity only when Shh and Netrin-1 were combined, indicating that SFKs can integrate the two guidance cues. Together, our results indicate that Shh and Netrin-1 synergize to enable growth cones to sense shallow gradients in regions of the spinal cord where the steepness of a single guidance cue is insufficient to guide axons, and we identify a novel type of synergy that occurs when the steepness (and not the concentration) of a guidance cue is limiting

Commissural axon turning depends more on the gradient fractional change than the concentration.

<p><b>(A)</b> Schematic of the concentration gradient within the microfluidic chamber. Because the concentration gradient is linear, the fractional change, δ, is highest when the concentration is low. Regardless of the maximum concentration used, the fractional change at a given position in the chamber is the same. <b>(B–E)</b> Both <b>(B)</b> Shh and <b>(C)</b> Netrin-1 gradients induce more turning as the fractional change increases. The average turned angle is plotted as a function of a moving window of 0.5% fractional change. Error bands represent mean and error of all neurons within the window at each position. The slope of the linear regression was 4.5 ± 2.0 degrees/% for Shh and 6.5 ± 2.4 degrees/% for Netrin. This increased turning response corresponds to an increase in the ratio of axons which turned in the correct direction in <b>(D)</b> Shh and <b>(E)</b> Netrin-1 gradients. (Shh: 43 < <i>n</i> ≤ 1,302; Netrin: 17 < <i>n</i> ≤ 569 from ≥ 4 independent microfluidic devices). <b>(F)</b> Circular distribution of individual turned angles. A random sample of 60 axons for Shh and 20 axons for Netrin-1 are plotted. For either cue, as the fractional change increases, turning is more robust, with a clear bias in the distribution of turned angles towards attraction and a decrease in the proportion of guidance errors. <b>(G, H)</b> For fractional change δ > 1%, there is no improvement in turning with increasing absolute local concentration of <b>(G)</b> Shh or <b>(H)</b> Netrin-1 at the growth cone. The number of axons in each group is indicated in parentheses. One-way ANOVA with Newman Keuls’ multiple comparison test indicated no significant differences between the groups. Scale bar <b>(F)</b>: 25 μm. Error bars represent SEM.</p

Shh and Netrin-1 synergize to guide commissural axons when their gradients are shallow.

<p><b>(A)</b> In shallow individual cue gradients, commissural axon turning is random (left and middle). In the presence of combined Shh and Netrin-1 shallow gradients (right), axons turn toward the higher concentration of guidance cue. When either gradient alone is insufficient to promote axon turning, pSFK activation is also not polarized up the gradient. However, the combined Shh and Netrin-1 gradient biases pSFK distribution to the side of the growth cone facing up the gradient. <b>(B)</b> In the developing spinal cord, the gradients of Shh and Netrin-1 proximal to the floor plate are steep (high fractional change), whereas further from the floor plate, the gradients of Shh and Netrin-1 are shallow (low fractional change). <b>(C)</b> When either the Shh or Netrin-1 signaling pathway is disabled, guidance errors occur at approximately the midpoint of the spinal cord, where the gradients are shallow. Our results suggest that in this shallow gradient region, integrating multiple guidance cues is necessary for correct growth cone guidance.</p

A combined gradient of Shh and Netrin-1 enhances axon guidance when the fractional change is sub-optimal for guidance towards a single cue.

<p><b>(A)</b> Average turned angle as a function of fractional change when axons are exposed to gradients for 45 h. Axons exposed to gradients of Shh (green) or Netrin-1 (blue) have a maximum response when the fractional change is at its highest, δ = 2.2%. A combined gradient of Shh and Netrin-1 (red) induce turning to a similar magnitude as either cue individually at δ = 2.2%, but induce turning that is higher than for either cue individually when the fractional change is below its maximum (1.4 < δ < 1.8%). Mean and error of the average turned angle within a window of 0.5% are shown (Shh: 31 < <i>n</i> ≤ 1,004; Netrin: 38 < <i>n</i> ≤ 1,107; Shh+Netrin: 40 < <i>n</i> ≤ 1,164). <b>(B)</b> We defined the synergy quotient as the ratio of the turning towards the combined gradient to the sum of the turning to either cue individually (calculated using the means from A). For the majority of the combined gradient, the combined influence is sub-additive. However, the combined cues act synergistically when the fractional change is (1.44 < δ < 1.82%), just below its maximum value. <b>(C)</b> At this fractional change (1.44 < δ < 1.82%), axons responded much more robustly than for either cue individually, resulting in a higher average turned angle. <b>(D)</b> The synergy observed when 1.44 < δ < 1.82% is consistent between independent experiments (Shh: <i>n</i> = 5; Netrin: <i>n</i> = 9; Shh+Netrin: <i>n</i> = 5; <i>p</i> = 0.043 one-way ANOVA with Newman-Keuls Multiple Comparison Test). <b>(E)</b> The increase in turned angle results from a larger ratio of axons turning toward than away from the gradient in the combined gradient (Shh: <i>n</i> = 55; Netrin: <i>n</i> = 92; Shh+Netrin: <i>n</i> = 73). <b>(F)</b> Angular distribution of the turned angles of a random sample of 60 neurons for 1.44 < δ < 1.82%. No bias in distribution is observed in the control gradient, nor in gradients of Shh or Netrin-1 alone. However, when axons are exposed to the combined gradient, there is a clear bias in the distribution of turned angles towards attraction. Therefore, in the presence of shallow combined gradients, there are fewer guidance errors occurring than for either cue individually. Scale bar <b>(F)</b>: 25 μm.</p