Parallel laboratory evolution and rational debugging reveal genomic plasticity to S. cerevisiae synthetic chromosome XIV defects

Synthetic chromosome engineering is a complex process due to the need to identify and repair growth defects and deal with combinatorial gene essentiality when rearranging chromosomes. To alleviate these issues, we have demonstrated novel approaches for repairing and rearranging synthetic Saccharomyces cerevisiae genomes. We have designed, constructed, and restored wild-type fitness to a synthetic 753,096-bp version of S. cerevisiae chromosome XIV as part of the Synthetic Yeast Genome project. In parallel to the use of rational engineering approaches to restore wild-type fitness, we used adaptive laboratory evolution to generate a general growth-defect-suppressor rearrangement in the form of increased TAR1 copy number. We also extended the utility of the synthetic chromosome recombination and modification by loxPsym-mediated evolution (SCRaMbLE) system by engineering synthetic-wild-type tetraploid hybrid strains that buffer against essential gene loss, highlighting the plasticity of the S. cerevisiae genome in the presence of rational and non-rational modifications. </p

Effect of early vasopressin vs norepinephrine on kidney failure in patients with septic shock. The VANISH Randomized Clinical Trial

IMPORTANCE: Norepinephrine is currently recommended as the first-line vasopressor in septic shock; however, early vasopressin use has been proposed as an alternative. OBJECTIVE: To compare the effect of early vasopressin vs norepinephrine on kidney failure in patients with septic shock. DESIGN, SETTING, AND PARTICIPANTS: A factorial (2×2), double-blind, randomized clinical trial conducted in 18 general adult intensive care units in the United Kingdom between February 2013 and May 2015, enrolling adult patients who had septic shock requiring vasopressors despite fluid resuscitation within a maximum of 6 hours after the onset of shock. INTERVENTIONS: Patients were randomly allocated to vasopressin (titrated up to 0.06 U/min) and hydrocortisone (n = 101), vasopressin and placebo (n = 104), norepinephrine and hydrocortisone (n = 101), or norepinephrine and placebo (n = 103). MAIN OUTCOMES AND MEASURES: The primary outcome was kidney failure-free days during the 28-day period after randomization, measured as (1) the proportion of patients who never developed kidney failure and (2) median number of days alive and free of kidney failure for patients who did not survive, who experienced kidney failure, or both. Rates of renal replacement therapy, mortality, and serious adverse events were secondary outcomes. RESULTS: A total of 409 patients (median age, 66 years; men, 58.2%) were included in the study, with a median time to study drug administration of 3.5 hours after diagnosis of shock. The number of survivors who never developed kidney failure was 94 of 165 patients (57.0%) in the vasopressin group and 93 of 157 patients (59.2%) in the norepinephrine group (difference, -2.3% [95% CI, -13.0% to 8.5%]). The median number of kidney failure-free days for patients who did not survive, who experienced kidney failure, or both was 9 days (interquartile range [IQR], 1 to -24) in the vasopressin group and 13 days (IQR, 1 to -25) in the norepinephrine group (difference, -4 days [95% CI, -11 to 5]). There was less use of renal replacement therapy in the vasopressin group than in the norepinephrine group (25.4% for vasopressin vs 35.3% for norepinephrine; difference, -9.9% [95% CI, -19.3% to -0.6%]). There was no significant difference in mortality rates between groups. In total, 22 of 205 patients (10.7%) had a serious adverse event in the vasopressin group vs 17 of 204 patients (8.3%) in the norepinephrine group (difference, 2.5% [95% CI, -3.3% to 8.2%]). CONCLUSIONS AND RELEVANCE: Among adults with septic shock, the early use of vasopressin compared with norepinephrine did not improve the number of kidney failure-free days. Although these findings do not support the use of vasopressin to replace norepinephrine as initial treatment in this situation, the confidence interval included a potential clinically important benefit for vasopressin, and larger trials may be warranted to assess this further. TRIAL REGISTRATION: clinicaltrials.gov Identifier: ISRCTN 20769191

Globalisation from Above? Corporate Social Responsibility, the Workers' Party and the Origins of the World Social Forum

In its assessment of the origins and early development of the World Social Forum this article challenges traditional understandings of the Forum as representing ‘globalisation from below’. By tracing the intricate relations among elements of business, civil society, and the Workers’ Party in the first years of the Forum, this article reveals the major role played by a corporate movement stemming from the Brazilian democratisation process in the 1980s, and how this combined with the transformed agenda of the Workers’ Party as it gained higher political offices to constrain the Forum’s activities from the outset. In so doing, this article challenges not only widespread conceptions of the Forum as a counter‐hegemonic alternative but also current critiques concerning its subsequent limitations. Furthermore, it reveals how traditional understandings of the World Social Forum and of global civil society are underpinned by flawed assumptions which typecast political activities in the global ‘South’

Geography, institutions and development: a review ofthe long-run impacts of climate change

The links between climate change, economic growth and economic development have gained increasing attention over recent years in both the academic and policy literature. However, most of the existing literature has tended to focus on direct, short run effects of climate change on the economy, for example due to extreme weather events and changes in agricultural growing conditions. In this paper we review potential effects of climate change on the prospects for long-run economic development. These effects might operate directly, via the role of geography (including climate) as a fundamental determinant of relative prosperity, or indirectly by modifying the environmental context in which political and economic institutions evolve. We consider potential mechanisms from climate change to long-run economic development that have been relatively neglected to date, including, for instance, effects on the distribution of income and political power. We conclude with some suggestions for areas of future research

CHEOPS and TESS view of the ultra-short period super-Earth TOI-561 b

Ultra-short period planets (USPs) are a unique class of super-Earths with an orbital period of less than a day and hence subject to intense radiation from their host star. While most of them are consistent with bare rocks, some show evidence of a heavyweight envelope, which could be a water layer or a secondary metal-rich atmosphere sustained by an outgassing surface. Much remains to be learned about the nature of USPs. The prime goal of the present work is to study the bulk planetary properties and atmosphere of TOI-561b, through the study of its transits and occultations. We obtained ultra-precise transit photometry of TOI-561b with CHEOPS and performed a joint analysis of this data with four TESS sectors. Our analysis of TOI-561b transit photometry put strong constraints on its properties, especially on its radius, Rp=1.42 +/- 0.02 R_Earth (at ~2% error). The internal structure modelling of the planet shows that the observations are consistent with negligible H/He atmosphere, however requiring other lighter materials, in addition to pure iron core and silicate mantle to explain the observed density. We find that this can be explained by the inclusion of a water layer in our model. We searched for variability in the measured Rp/R* over time to trace changes in the structure of the planetary envelope but none found within the data precision. In addition to the transit event, we tentatively detect occultation signal in the TESS data with an eclipse depth of ~27 +/- 11 ppm. Using the models of outgassed atmospheres from the literature we find that the thermal emission from the planet can mostly explain the observation. Based on this, we predict that NIR/MIR observations with JWST should be able to detect silicate species in the atmosphere of the planet. This could also reveal important clues about the planetary interior and help disentangle planet formation and evolution models.Comment: 17 pages, 10 + 3 figures, 4 tables, accepted for publication in A&A (abstract abbreviated

A CHEOPS-enhanced view of the HD 3167 system

A. C. C. and T. G. W. acknowledge support from STFC consolidated grant numbers ST/R000824/1 and ST/V000861/1, and UKSA grant number ST/R003203/1.Much remains to be understood about the nature of exoplanets smaller than Neptune, most of which have been discovered in compact multi-planet systems. With its inner ultra-short period planet b aligned with the star and two larger outer planets d-c on polar orbits, the multi-planet system HD 3167 features a peculiar architecture and offers the possibility to investigate both dynamical and atmospheric evolution processes. To this purpose we combined multiple datasets of transit photometry and radial velocimetry (RV) to revise the properties of the system and inform models of its planets. This effort was spearheaded by CHEOPS observations of HD 3167b, which appear inconsistent with a purely rocky composition despite its extreme irradiation. Overall the precision on the planetary orbital periods are improved by an order of magnitude, and the uncertainties on the densities of the transiting planets b and c are decreased by a factor of 3. Internal structure and atmospheric simulations draw a contrasting picture between HD 3167d, likely a rocky super-Earth that lost its atmosphere through photo-evaporation, and HD 3167c, a mini-Neptune that kept a substantial primordial gaseous envelope. We detect a fourth, more massive planet on a larger orbit, likely coplanar with HD 3167d-c. Dynamical simulations indeed show that the outer planetary system d-c-e was tilted, as a whole, early in the system history, when HD 3167b was still dominated by the star influence and maintained its aligned orbit. RV data and direct imaging rule out that the companion that could be responsible for the present-day architecture is still bound to the HD 3167 system. Similar global studies of multi-planet systems will tell how many share the peculiar properties of the HD 3167 system, which remains a target of choice for follow-up observations and simulations. © 2022 EDP Sciences. All rights reserved.Publisher PDFPeer reviewe

A CHEOPS-enhanced view of the HD3167 system

Much remains to be understood about the nature of exoplanets smaller than Neptune, most of which have been discovered in compact multi-planet systems. With its inner ultra-short period planet b aligned with the star and two larger outer planets d-c on polar orbits, the multi-planet system HD 3167 features a peculiar architecture and offers the possibility to investigate both dynamical and atmospheric evolution processes. To this purpose we combined multiple datasets of transit photometry and radial velocimetry (RV) to revise the properties of the system and inform models of its planets. This effort was spearheaded by CHEOPS observations of HD 3167b, which appear inconsistent with a purely rocky composition despite its extreme irradiation. Overall the precision on the planetary orbital periods are improved by an order of magnitude, and the uncertainties on the densities of the transiting planets b and c are decreased by a factor of 3. Internal structure and atmospheric simulations draw a contrasting picture between HD 3167d, likely a rocky super-Earth that lost its atmosphere through photo-evaporation, and HD 3167c, a mini-Neptune that kept a substantial primordial gaseous envelope. We detect a fourth, more massive planet on a larger orbit, likely coplanar with HD 3167d-c. Dynamical simulations indeed show that the outer planetary system d-c-e was tilted, as a whole, early in the system history, when HD 3167b was still dominated by the star influence and maintained its aligned orbit. RV data and direct imaging rule out that the companion that could be responsible for the present-day architecture is still bound to the HD\,3167 system. Similar global studies of multi-planet systems will tell how many share the peculiar properties of the HD3167 system, which remains a target of choice for follow-up observations and simulations.Comment: 22 pages, 23 pages, accepted for publication in A&A (18 August 2022). Updated author list in new versio

Refining the properties of the TOI-178 system with CHEOPS and TESS

The TOI-178 system consists of a nearby late K-dwarf transited by six planets in the super-Earth to mini-Neptune regime, with orbital periods between 1.9 and 20.7 days. All planets but the innermost one form a chain of Laplace resonances. Mass estimates derived from a preliminary radial velocity (RV) dataset suggest that the planetary densities do not decrease in a monotonic way with the orbital distance to the star, contrary to what one would expect based on simple formation and evolution models. To improve the characterisation of this key system and prepare for future studies (in particular with JWST), we perform a detailed photometric study based on 40 new CHEOPS visits, one new TESS sector, as well as previously published CHEOPS, TESS, and NGTS data. First we perform a global analysis of the 100 transits contained in our data to refine the transit parameters of the six planets and study their transit timing variations (TTVs). We then use our extensive dataset to place constraints on the radii and orbital periods of potential additional transiting planets in the system. Our analysis significantly refines the transit parameters of the six planets, most notably their radii, for which we now obtain relative precisions $\lesssim$3%, with the exception of the smallest planet $b$ for which the precision is 5.1%. Combined with the RV mass estimates, the measured TTVs allow us to constrain the eccentricities of planets $c$ to $g$, which are found to be all below 0.02, as expected from stability requirements. Taken alone, the TTVs also suggest a higher mass for planet $d$ than the one estimated from the RVs, which had been found to yield a surprisingly low density for this planet. However, the masses derived from the current TTV dataset are very prior-dependent and further observations, over a longer temporal baseline, are needed to deepen our understanding of this iconic planetary system.Comment: 20 pages, 5 figures, 9 tables. Accepted for publication in A&

Decreasing incidence of peptic ulcer complications after the introduction of the proton pump inhibitors, a study of the Swedish population from 1974–2002

<p>Abstract</p> <p>Background</p> <p>Despite a decreasing incidence of peptic ulcer disease, most previous studies report a stabile incidence of ulcer complications. We wanted to investigate the incidence of peptic ulcer complications in Sweden before and after the introduction of the proton pump inhibitors (PPI) in 1988 and compare these data to the sales of non-steroid anti-inflammatory drugs (NSAID) and acetylsalicylic acid (ASA).</p> <p>Methods</p> <p>All cases of gastric and duodenal ulcer complications diagnosed in Sweden from 1974 to 2002 were identified using the National hospital discharge register. Information on sales of ASA/NSAID was obtained from the National prescription survey.</p> <p>Results</p> <p>When comparing the time-periods before and after 1988 we found a significantly lower incidence of peptic ulcer complications during the later period for both sexes (p < 0.001). Incidence rates varied from 1.5 to 7.8/100000 inhabitants/year regarding perforated peptic ulcers and from 5.2 to 40.2 regarding peptic ulcer bleeding. The number of sold daily dosages of prescribed NSAID/ASA tripled from 1975 to 2002. The number of prescribed sales to women was higher than to males. Sales of low-dose ASA also increased. The total volume of NSAID and ASA, i.e. over the counter sale and sold on prescription, increased by 28% during the same period.</p> <p>Conclusion</p> <p>When comparing the periods before and after the introduction of the proton pump inhibitors we found a significant decrease in the incidence of peptic ulcer complications in the Swedish population after 1988 when PPI were introduced on the market. The cause of this decrease is most likely multifactorial, including smoking habits, NSAID consumption, prevalence of Helicobacter pylori and the introduction of PPI. Sales of prescribed NSAID/ASA increased, especially in middle-aged and elderly women. This fact seems to have had little effect on the incidence of peptic ulcer complications.</p