Inactivation of a Single Copy of Crebbp Selectively Alters Pre-mRNA Processing in Mouse Hematopoietic Stem Cells

Global expression analysis of fetal liver hematopoietic stem cells (FL HSCs) revealed the presence of unspliced pre-mRNA for a number of genes in normal FL HSCs. In a subset of these genes, Crebbp+/− FL HSCs had less unprocessed pre-mRNA without a corresponding reduction in total mRNA levels. Among the genes thus identified were the key regulators of HSC function Itga4, Msi2 and Tcf4. A similar but much weaker effect was apparent in Ep300+/− FL HSCs, indicating that, in this context as in others, the two paralogs are not interchangeable. As a group, the down-regulated intronic probe sets could discriminate adult HSCs from more mature cell types, suggesting that the underlying mechanism is regulated with differentiation stage and is active in both fetal and adult hematopoiesis. Consistent with increased myelopoiesis in Crebbp hemizygous mice, targeted reduction of CREBBP abundance by shRNA in the multipotent EML cell line triggered spontaneous myeloid differentiation in the absence of the normally required inductive signals. In addition, differences in protein levels between phenotypically distinct EML subpopulations were better predicted by taking into account not only the total mRNA signal but also the amount of unspliced message present. CREBBP thus appears to selectively influence the timing and degree of pre-mRNA processing of genes essential for HSC regulation and thereby has the potential to alter subsequent cell fate decisions in HSCs

Microbiome to Brain:Unravelling the Multidirectional Axes of Communication

The gut microbiome plays a crucial role in host physiology. Disruption of its community structure and function can have wide-ranging effects making it critical to understand exactly how the interactive dialogue between the host and its microbiota is regulated to maintain homeostasis. An array of multidirectional signalling molecules is clearly involved in the host-microbiome communication. This interactive signalling not only impacts the gastrointestinal tract, where the majority of microbiota resides, but also extends to affect other host systems including the brain and liver as well as the microbiome itself. Understanding the mechanistic principles of this inter-kingdom signalling is fundamental to unravelling how our supraorganism function to maintain wellbeing, subsequently opening up new avenues for microbiome manipulation to favour desirable mental health outcome

Keynes’ Grandchildren and Easterlin’s Paradox. What Is Keeping Us from Reducing Our Working Hours?

In 1930 Keynes famously predicted that 100 years later-i.e. in 2030-the “economic problem” would be solved and we would be living in an “age of leisure and of abundance” working only 3 h a day. In the same text, Keynes stated that there are absolute and relative needs (“in the sense that we feel them only if their satisfaction lifts us above, makes us feel superior to, our fellows”), but he thought that relative needs are of minor importance. Richard Easterlin’s work, on the other hand, suggests that relative needs are pervasive and that wellbeing depends much more on one’s relative income than Keynes once thought. It will be argued in this text that Richard Easterlin’s findings, in spite of proving Keynes off the mark in his understatement of relative needs, strengthens the case for working time reductions: the larger the proportion of goods subject to the relative-income effect, the greater are the benefits of working fewer hours. Perhaps the main explanation for why we are still sticking to the 40-h work-week is that the Easterlin paradox has not been widely understood yet