FoxG1 antagonizes neocortical stem cell progression to astrogenesis

Neocortical astrogenesis follows neuronogenesis and precedes oligogenesis. Among key factors dictating its temporal articulation, there are progression rates of pallial stem cells (SCs) towards astroglial lineages as well as activation rates of astrocyte differentiation programs in response to extrinsic gliogenic cues. In this study, we showed that high Foxg1 SC expression antagonizes astrocyte generation, while stimulating SC self-renewal and committing SCs to neuronogenesis. We found that mechanisms underlying this activity are mainly cell autonomous and highly pleiotropic. They include a concerted downregulation of 4 key effectors channeling neural SCs to astroglial fates, as well as defective activation of core molecular machineries implementing astroglial differentiation programs. Next, we found that SC Foxg1 levels specifically decline during the neuronogenic-to-gliogenic transition, pointing to a pivotal Foxg1 role in temporal modulation of astrogenesis. Finally, we showed that Foxg1 inhibits astrogenesis from human neocortical precursors, suggesting that this is an evolutionarily ancient trait

No detection of methane on Mars from early ExoMars Trace Gas Orbiter observations

The detection of methane on Mars has been interpreted as indicating that geochemical or biotic activities could persist on Mars today. A number of different measurements of methane show evidence of transient, locally elevated methane concentrations and seasonal variations in background methane concentrations. These measurements, however, are difficult to reconcile with our current understanding of the chemistry and physics of the Martian atmosphere, which-given methane's lifetime of several centuries-predicts an even, well mixed distribution of methane. Here we report highly sensitive measurements of the atmosphere of Mars in an attempt to detect methane, using the ACS and NOMAD instruments onboard the ESA-Roscosmos ExoMars Trace Gas Orbiter from April to August 2018. We did not detect any methane over a range of latitudes in both hemispheres, obtaining an upper limit for methane of about 0.05 parts per billion by volume, which is 10 to 100 times lower than previously reported positive detections. We suggest that reconciliation between the present findings and the background methane concentrations found in the Gale crater would require an unknown process that can rapidly remove or sequester methane from the lower atmosphere before it spreads globally

Martian dust storm impact on atmospheric H₂O and D/H observed by ExoMars Trace Gas Orbiter

Global dust storms on Mars are rare but can affect the Martian atmosphere for several months. They can cause changes in atmospheric dynamics and inflation of the atmosphere, primarily owing to solar heating of the dust. In turn, changes in atmospheric dynamics can affect the distribution of atmospheric water vapour, with potential implications for the atmospheric photochemistry and climate on Mars. Recent observations of the water vapour abundance in the Martian atmosphere during dust storm conditions revealed a high-altitude increase in atmospheric water vapour that was more pronounced at high northern latitudes, as well as a decrease in the water column at low latitudes. Here we present concurrent, high-resolution measurements of dust, water and semiheavy water (HDO) at the onset of a global dust storm, obtained by the NOMAD and ACS instruments onboard the ExoMars Trace Gas Orbiter. We report the vertical distribution of the HDO/H O ratio (D/H) from the planetary boundary layer up to an altitude of 80 kilometres. Our findings suggest that before the onset of the dust storm, HDO abundances were reduced to levels below detectability at altitudes above 40 kilometres. This decrease in HDO coincided with the presence of water-ice clouds. During the storm, an increase in the abundance of H2O and HDO was observed at altitudes between 40 and 80 kilometres. We propose that these increased abundances may be the result of warmer temperatures during the dust storm causing stronger atmospheric circulation and preventing ice cloud formation, which may confine water vapour to lower altitudes through gravitational fall and subsequent sublimation of ice crystals. The observed changes in H2O and HDO abundance occurred within a few days during the development of the dust storm, suggesting a fast impact of dust storms on the Martian atmosphere

FOXG1 modulates LINE1 activity in the developing embryonic neocortex

Foxg1 is an ancient transcription factor mastering telencephalic development. mLINE1 is a large retrotransposon family contributing to plasticity of neuronal genome. All mLINE1's share putative Foxg1 binding elements. Moreover, it is known that mLINE1 transcription is upregulated in postnatal glutamatergic progenitors, whereas Foxg1 declines in embryonic progenitors of the same lineage. Based on that, we predicted that Foxg1 might limit mLINE1 expression (and activity). Here we tested such prediction, with particular attention to its cellular and molecular features. First, as expected, we found that mLINE1-mRNA encoded by all three retro-transposition competent subfamilies (A, Gf and Tf) was increased in Foxg1-loss-of-function (-LOF) mouse pups. Next, to model articulation of Foxg1-dependent LINE1 regulation, we developed a dedicated set of in vitro preparations, representing early-, mid- and late-phases of neuronogenesis. By profiling this set, we detected a progressive increase of LINE1-mRNA levels from neural stem cells (NSCs) up to neurons (Ns). Then, taking advantage of these preparations, we manipulated Foxg1 levels at different stages of the neuronogenic progression, according to specific neural cell type restrictions. We mapped changes in Foxg1 protein levels evoked of these manipulations, and we evaluated LINE1-mRNA levels originating from them. Integrated analysis of results pointed to selective mLINE1 repression by Foxg1 in neuronal progenitors (NPs) and Ns. To assess if Foxg1 modulation of mLINE1-mRNA takes place via direct gene trans-repression, we evaluated Foxg1 enrichment at mLINE1 loci via ChIP. In wild type cultures, Foxg1 was enriched along the whole body of mLINE1's belonging to all three subfamilies. However, this enrichment was restricted to mid-neuronogenic cultures, and not detectable in early-neuronogenic ones, ruling out Foxg1 modulation of mLINEs in NSCs. Intriguingly, such enrichment was more pronounced upon artificial Foxg1 overexpression, suggesting that Foxg1 may physiologically tune mLINE1 transcription. Furthermore, we found that Foxg1 overexpression in mid-neuronogenic cultures elicited a generalized decrease in transcription-activating marks (H3K4me3) and an increase of repressing ones (H3K9me3). These phenomena occurred at all mLINE1 subfamilies loci, suggesting that Foxg1 largely impacts on mLINE1 transcription via modifications of the corresponding epigenetic landscape. Next, we moved to Foxg1 control (if any) of cellular mLINE1-DNA content. First, we found that this content was upregulated by about 25% in Tubb3+, post-mitotic wild type neurons compared to their ancestors, in a retro-transcription-dependent way. Next, paradoxically, we also discovered that Foxg1 down-regulation elicited a co-linear reduction in mLINE1-DNA content, suggesting that Foxg1 is strictly needed to sustain physiological amplification of such DNA. This phenomenon was observed in vivo as well as in vitro. Puzzingly, Foxg1 overexpression led to variable outcomes, increased, unchanged or decreased mLINE1-DNA content, depending on different promoters driving it. Differential sensitivity of mLINE1 transcription and retro-transcription to Foxg1 levels could account for these phenomena. Finally, mechanisms underlying Foxg1 impact on mLINE1 DNA content were not yet investigated, however, we got evidence that direct Foxg1 protein/mLINE1-mRNA interaction could underlie it

Sonographic hepatic-renal ratio as indicator of hepatic steatosis: comparison with (1)H magnetic resonance spectroscopy.

The aim of this study was to determine the diagnostic performance of ultrasound (US) in the quantitative assessment of steatosis by comparison with proton magnetic resonance spectroscopy ((1)H-MRS) as a reference standard. Three liver echo-intensity indices were derived: US hepatic mean gray level, hepatic-renal echo-intensity ratio (H/R), and hepatic-portal blood echo-intensity ratio. The (1)H-MRS degree of steatosis was determined as percentage fat by wet weight. Regression equations were used to estimate quantitatively hepatic fat content. The hepatic fat content by (1)H-MRS analysis ranged from 0.10% to 28.9% (median value, 4.8%). Ultrasound H/R was correlated with the degree of steatosis on (1)H-MRS (R(2)= 0.92; P < .0001), whereas no correlation with (1)H-MRS was found for hepatic mean gray level and hepatic-portal blood echo-intensity ratio. A receiver operating characteristic curve identified the H/R of 2.2 as the best cutoff point for the prediction of (1)H-MRS of at least 5%, yielding measures of sensitivity and specificity of 100% and 95%, respectively. In this pilot study, US H/R exhibits high sensitivity and specificity for detecting liver fatty changes. Our results indicate that quantitative evaluation of hepatic fat content can be performed using US H/R and could therefore be a valuable analytic tool in clinical investigation

Tocilizumab for patients with COVID-19 pneumonia. The single-arm TOCIVID-19 prospective trial

BackgroundTocilizumab blocks pro-inflammatory activity of interleukin-6 (IL-6), involved in pathogenesis of pneumonia the most frequent cause of death in COVID-19 patients.MethodsA multicenter, single-arm, hypothesis-driven trial was planned, according to a phase 2 design, to study the effect of tocilizumab on lethality rates at 14 and 30 days (co-primary endpoints, a priori expected rates being 20 and 35%, respectively). A further prospective cohort of patients, consecutively enrolled after the first cohort was accomplished, was used as a secondary validation dataset. The two cohorts were evaluated jointly in an exploratory multivariable logistic regression model to assess prognostic variables on survival.ResultsIn the primary intention-to-treat (ITT) phase 2 population, 180/301 (59.8%) subjects received tocilizumab, and 67 deaths were observed overall. Lethality rates were equal to 18.4% (97.5% CI: 13.6-24.0, P=0.52) and 22.4% (97.5% CI: 17.2-28.3, P<0.001) at 14 and 30 days, respectively. Lethality rates were lower in the validation dataset, that included 920 patients. No signal of specific drug toxicity was reported. In the exploratory multivariable logistic regression analysis, older age and lower PaO2/FiO2 ratio negatively affected survival, while the concurrent use of steroids was associated with greater survival. A statistically significant interaction was found between tocilizumab and respiratory support, suggesting that tocilizumab might be more effective in patients not requiring mechanical respiratory support at baseline.ConclusionsTocilizumab reduced lethality rate at 30 days compared with null hypothesis, without significant toxicity. Possibly, this effect could be limited to patients not requiring mechanical respiratory support at baseline.Registration EudraCT (2020-001110-38); clinicaltrials.gov (NCT04317092)