The trophectoderm acts as a niche for the inner cell mass through C/EBPα-regulated IL-6 signaling

Gene regulation; Somatic cell reprogramming; TrophectodermRegulación de genes; Reprogramación de células somáticas; TrofoectodermoRegulació de gens; Reprogramació de cèl·lules somàtiques; TrofectodermaIL-6 has been shown to be required for somatic cell reprogramming into induced pluripotent stem cells (iPSCs). However, how Il6 expression is regulated and whether it plays a role during embryo development remains unknown. Here, we describe that IL-6 is necessary for C/EBPα-enhanced reprogramming of B cells into iPSCs but not for B cell to macrophage transdifferentiation. C/EBPα overexpression activates both Il6 and Il6ra genes in B cells and in PSCs. In embryo development, Cebpa is enriched in the trophectoderm of blastocysts together with Il6, while Il6ra is mostly expressed in the inner cell mass (ICM). In addition, Il6 expression in blastocysts requires Cebpa. Blastocysts secrete IL-6 and neutralization of the cytokine delays the morula to blastocyst transition. The observed requirement of C/EBPα-regulated IL-6 signaling for pluripotency during somatic cell reprogramming thus recapitulates a physiologic mechanism in which the trophectoderm acts as niche for the ICM through the secretion of IL-6.We thank C. Berenguer for help with B cell reprogramming and bone marrow collection; S. Nakagawa and B. Pernaute for advice on pre-implantation embryo culture and manipulation, and Kyle M. Loh for his valuable discussions; the flow cytometry and microscopy units of UPF-CRG for technical assistance; the CRG genomics core facility for sequencing and Graf laboratory members for critical discussions. Work in the laboratory of T.G. was supported by the Spanish Ministry of Economy, Industry and Competitiveness (Plan Estatal PID2019-109354GB-I00), the CRG, AGAUR (SGR 726), and a European Research Council Synergy grant (4D-Genome). M.P.-C. was supported by an FPI fellowship (BES-2016-076900). Work in the laboratory of M.S. was funded by the IRB and by grants from the Spanish Ministry of Economy co-funded by the European Regional Development Fund (SAF2017-82613-R), ERC (ERC-2014-AdG/669622), la Caixa Foundation, and Secretaria d’Universitats i Recerca del Departament d’Empresa i Coneixement of Catalonia (Grup de Recerca consolidat 2017 SGR 282)

The trophectoderm acts as a niche for the inner cell mass through C/EBPα-regulated IL-6 signaling

IL-6 has been shown to be required for somatic cell reprogramming into induced pluripotent stem cells (iPSCs). However, how Il6 expression is regulated and whether it plays a role during embryo development remains unknown. Here, we describe that IL-6 is necessary for C/EBPα-enhanced reprogramming of B cells into iPSCs but not for B cell to macrophage transdifferentiation. C/EBPα overexpression activates both Il6 and Il6ra genes in B cells and in PSCs. In embryo development, Cebpa is enriched in the trophectoderm of blastocysts together with Il6, while Il6ra is mostly expressed in the inner cell mass (ICM). In addition, Il6 expression in blastocysts requires Cebpa. Blastocysts secrete IL-6 and neutralization of the cytokine delays the morula to blastocyst transition. The observed requirement of C/EBPα-regulated IL-6 signaling for pluripotency during somatic cell reprogramming thus recapitulates a physiologic mechanism in which the trophectoderm acts as niche for the ICM through the secretion of IL-6.Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved

CO or no CO? Narrowing the CO abundance constraint and recovering the H2O detection in the atmosphere of WASP-127 b using SPIRou

Precise measurements of chemical abundances in planetary atmospheres are necessary to constrain the formation histories of exoplanets. A recent study of WASP-127b, a close-in puffy sub-Saturn orbiting its solar-type host star in 4.2 d, using HST and Spitzer revealed a feature-rich transmission spectrum with strong excess absorption at 4.5 um. However, the limited spectral resolution and coverage of these instruments could not distinguish between CO and/or CO2 absorption causing this signal, with both low and high C/O ratio scenarios being possible. Here we present near-infrared (0.9--2.5 um) transit observations of WASP-127 b using the high-resolution SPIRou spectrograph, with the goal to disentangle CO from CO2 through the 2.3 um CO band. With SPIRou, we detect H2O at a t-test significance of 5.3 sigma and observe a tentative (3 sigma) signal consistent with OH absorption. From a joint SPIRou + HST + Spitzer retrieval analysis, we rule out a CO-rich scenario by placing an upper limit on the CO abundance of log10[CO]<-4.0, and estimate a log10[CO2] of -3.7^(+0.8)_(-0.6), which is the level needed to match the excess absorption seen at 4.5um. We also set abundance constraints on other major C-, O-, and N-bearing molecules, with our results favoring low C/O (0.10^(+0.10)_(-0.06)), disequilibrium chemistry scenarios. We further discuss the implications of our results in the context of planet formation. Additional observations at high and low-resolution will be needed to confirm these results and better our understanding of this unusual world.Comment: 23 pages, 13 figures, Submitted for publication in the Monthly Notice of the Royal Astronomical Societ

Risk of intracranial haemorrhage and ischaemic stroke after convexity subarachnoid haemorrhage in cerebral amyloid angiopathy : international individual patient data pooled analysis

Altres ajuts: JF reports grants from Instituto de Salud Carlos III, grants from Fundació Marató TV3, grants from NIH, grants from Departament de Salut de la Generalitat de Catalunya.To investigate the frequency, time-course and predictors of intracerebral haemorrhage (ICH), recurrent convexity subarachnoid haemorrhage (cSAH), and ischemic stroke after cSAH associated with cerebral amyloid angiopathy (CAA). We performed a systematic review and international individual patient-data pooled analysis in patients with cSAH associated with probable or possible CAA diagnosed on baseline MRI using the modified Boston criteria. We used Cox proportional hazards models with a frailty term to account for between-cohort differences. We included 190 patients (mean age 74.5 years; 45.3% female) from 13 centers with 385 patient-years of follow-up (median 1.4 years). The risks of each outcome (per patient-year) were: ICH 13.2% (95% CI 9.9-17.4); recurrent cSAH 11.1% (95% CI 7.9-15.2); combined ICH, cSAH, or both 21.4% (95% CI 16.7-26.9), ischemic stroke 5.1% (95% CI 3.1-8) and death 8.3% (95% CI 5.6-11.8). In multivariable models, there is evidence that patients with probable CAA (compared to possible CAA) had a higher risk of ICH (HR 8.45, 95% CI 1.13-75.5, p = 0.02) and cSAH (HR 3.66, 95% CI 0.84-15.9, p = 0.08) but not ischemic stroke (HR 0.56, 95% CI 0.17-1.82, p = 0.33) or mortality (HR 0.54, 95% CI 0.16-1.78, p = 0.31). Patients with cSAH associated with probable or possible CAA have high risk of future ICH and recurrent cSAH. Convexity SAH associated with probable (vs possible) CAA is associated with increased risk of ICH, and cSAH but not ischemic stroke. Our data provide precise risk estimates for key vascular events after cSAH associated with CAA which can inform management decisions. The online version contains supplementary material available at 10.1007/s00415-021-10706-3

Photography-based taxonomy is inadequate, unnecessary, and potentially harmful for biological sciences

The question whether taxonomic descriptions naming new animal species without type specimen(s) deposited in collections should be accepted for publication by scientific journals and allowed by the Code has already been discussed in Zootaxa (Dubois & Nemésio 2007; Donegan 2008, 2009; Nemésio 2009a–b; Dubois 2009; Gentile & Snell 2009; Minelli 2009; Cianferoni & Bartolozzi 2016; Amorim et al. 2016). This question was again raised in a letter supported by 35 signatories published in the journal Nature (Pape et al. 2016) on 15 September 2016. On 25 September 2016, the following rebuttal (strictly limited to 300 words as per the editorial rules of Nature) was submitted to Nature, which on 18 October 2016 refused to publish it. As we think this problem is a very important one for zoological taxonomy, this text is published here exactly as submitted to Nature, followed by the list of the 493 taxonomists and collection-based researchers who signed it in the short time span from 20 September to 6 October 2016

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707

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

Social inequality in incidence and mortality of malignant neoplasms of lip, oral cavity and pharynx: Is Costa Rica an international paradox?

Objectives: Low socioeconomic position (SEP) has been associated with higher incidences and mortality of lip, oral cavity and pharynx (LOP) cancers in the vast majority of countries with available data. The origins of health inequalities in cancer are socioeconomic, although they vary by time and country. Evidence from Low-and Middle-income Countries (LMICs) remains scarce. This study aims to identify and describe socioeconomic inequalities in LOP cancers incidence and mortality in Costa Rica. The hypothesis tested is that people leaving in low-SEP districts in Costa Rica have greater incidence and mortality rates of lip, oral cavity and pharynx cancers. Methods: The 10th revision of the International Classification of Diseases (ICD-10) was used to define cancer sites. Data come from a national population-based Cancer Registry with 100% completeness to study incidence. Incidence rate included all new cases of LOP cancer diagnosed from January 1, 2011, and December 31, 2015, for a total of 2 798 517 individuals, 13 832 524 years of follow-up and 601 LOP cases. Mortality rate was extracted from the National Death Index, including 2 739 733 individuals, 23 950 240 person-years of follow-up and 586 LOP cancer deaths, from January 1, 2010, to December 31, 2018. The 2011 Census (with 94% of Costa Rican inhabitants) was used to characterize the urbanicity and wealth of 477 districts. Survival models were performed for both incidence and mortality, allowing to consider existing competitive risks. Cox models were used for incidence, and parametric survival models based on a Gompertz distribution for mortality. Results: The study found that people who lived in the most socioeconomically disadvantaged areas had lower probabilities of developing LOP cancers than people in the richest districts. The same pattern for mortality, however, was not significant. Conclusions: The hypothesis that incidence and mortality of LOP cancers will show a positive social gradient was not confirmed in this study, contradicting the existing literature. This could be explained by the social distribution of risky health behaviours, more frequent in socially advantaged populations.Universidad de Costa RicaUCR::Vicerrectoría de Docencia::Salud::Facultad de OdontologíaUCR::Vicerrectoría de Docencia::Salud::Facultad de Medicina::Escuela de Salud PúblicaUCR::Vicerrectoría de Docencia::Salud::Facultad de Medicina::Escuela de Medicin

On the Characterization of Jitter in Ring Oscillators using Allan variance for True Random Number Generator Applications

International audienceThe description of the physical noise source is of utmost importance for any TRNG certification. In the case of ring oscillators, Allan variance is a reliable and comprehensive tool which enables the distinction between the jitter coming from flicker noise (autocorrelated) and from thermal noise (random). In this paper, we realize measurements directly on the analog source of numerous TRNG structures: a ring oscillator. Our data, along with evidence from the literature, indicates the presence of a third noise source. The quantization noise has not been so far taken into consideration, but is unquestionably present in all TRNG reliant on jitter. Its importance is key to an accurate estimation of thermal noise contribution, which can be shadowed by it. Measurements presented in this paper show that insufficient sampling (i.e. higher quantization noise) can lead to an overestimation of jitter coming from thermal noise and therefore an overestimation of the calculated entropy. The latter is the only type of noise considered reliable in currently existing ring oscillator-based TRNG models. As a rule of thumb, three orders of magnitude between the sampling and the sampled signal are necessary in order to determine the thermal noise jitter correctly