p107 regulates neural precursor cells in the mammalian brain

Here we show a novel function for Retinoblastoma family member, p107 in controlling stem cell expansion in the mammalian brain. Adult p107-null mice had elevated numbers of proliferating progenitor cells in their lateral ventricles. In vitro neurosphere assays revealed striking increases in the number of neurosphere forming cells from p107−/− brains that exhibited enhanced capacity for self-renewal. An expanded stem cell population in p107-deficient mice was shown in vivo by (a) increased numbers of slowly cycling cells in the lateral ventricles; and (b) accelerated rates of neural precursor repopulation after progenitor ablation. Notch1 was up-regulated in p107−/− neurospheres in vitro and brains in vivo. Chromatin immunoprecipitation and p107 overexpression suggest that p107 may modulate the Notch1 pathway. These results demonstrate a novel function for p107 that is distinct from Rb, which is to negatively regulate the number of neural stem cells in the developing and adult brain

A trajectory modeling investigation of the biomass burning-tropical ozone relationship

The hypothesis that tropical total O3 maxima seen by the TOMS satellite derive from African biomass burning has been tested using isentropic trajectory analyses with global meteorological data fields. Two case studies from the 1989 biomass burning season demonstrate that a large fraction of the air arriving at the location of TOMS O3 maxima passed over regions of intense burning. Other trajectories initiated at a series of points over Africa and the Atlantic suggest flight strategies for field studies to be conducted in September 1992

Pleasure in decision-making situations

BACKGROUND: This study explores the role of pleasure in decision making. RESULTS: In Experiment 1, 12 subjects were presented with a questionnaire containing 46 items taken from the literature. Twenty-three items described a situation where a decision should be made and ended with a suggested solution. The other items served as filler items. The subjects were requested not to make a decision but to rate the pleasure or displeasure they experienced when reading the situation described in the item. The subjects' ratings were then compared to the decisions on the same situations made by the other subjects of the studies published by other workers. The ratings of pleasure/displeasure given by our subjects correlated significantly with the choices published by other authors. This result satisfies a necessary condition for pleasure to be the key of the decision making process in theoretical situations. In Experiment 2, a new group of 12 subjects rated their experience of pleasure/displeasure when reading various versions of 50 situations taken from daily life where an ethical decision had to be made (Questionnaire I) including 200 items. This was followed by a multiple-choice test with the 50 situations (Questionnaire II) using the same 200 items and offering the various behaviors. Subjects tended to choose ethical and unethical responses corresponding to their highest pleasure rating within each problem. In all cases the subjects' behavior was higher than chance level, and thus, followed the trend to maximize pleasure. In Experiment 3, 12 subjects reading 50 mathematical short problems followed by correct and incorrect versions of the answer to the problem (Questionnaire III), including 200 items. This was followed by a multiple-choice mathematical test with the 50 problems (Questionnaire IV) using the same 200 items and offering the correct and incorrect answers. In questionnaire IV, subjects tended to choose correct as well as incorrect responses corresponding to their highest hedonic rating within each problem. In all cases the subjects' behavior was higher than chance level, and thus, followed the trend to maximize pleasure. CONCLUSIONS: The results of the three experiments support the hypothesis according to which decisions are made in the hedonic dimension of conscious experience

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

The European rescue of the Washington Consensus? EU and IMF lending to Central and Eastern European countries

The latest global financial crisis has allowed the International Monetary Fund (IMF) a spectacular comeback. But despite its notorious reputation as a staunch advocate of restrictive economic policies, the Fund has displayed less preference for austerity in recent crisis lending. Though widely welcomed as overdue, the IMF’s shift away from what John Williamson coined the ‘Washington Consensus’ was met with resistance from the European Union (EU) where it concerned Central and Eastern European (CEE) countries. The situation of hard-hit Hungary, Latvia, and Romania propelled unprecedented cooperation between the IMF and the EU, in which the EU has very actively promoted orthodox measures in return for loans. We argue that this represents a European rescue of the Washington Consensus. The case of Latvia is paradigmatic for the profound disagreements between an austerity-demanding EU and a less austere IMF. The IMF’s stance contradicts conventional wisdom about the organization as the guardian of economic orthodoxy. To solve this puzzle, we shed light on three complementary factors of (non)learning that have shaped the EU’s relations vis-à-vis CEE borrowing countries in comparison to the IMF’s: (1) a disadvantageous institutional setting; (2) vociferous creditor coalitions; (3) the precarious eurozone project