The Noxa/Mcl-1 Axis Regulates Susceptibility to Apoptosis under Glucose Limitation in Dividing T Cells

SummaryThroughout lymphocyte development, cellular persistence and expansion are tightly regulated by survival and apoptosis. Within the Bcl-2 family, distinct apoptogenic BH3-only members like Bid, Bim, and Puma appear to function in specific cell death pathways. We found that naive human T cells after mitogenic activation, apart from expected protective Bcl-2 members, also rapidly upregulate the BH3-only protein Noxa in a p53-independent fashion. The specific role of Noxa became apparent during glucose limitation and involves interaction with the labile Bcl-2 homolog Mcl-1. Knockdown of Noxa or Mcl-1 results in protection or susceptibility, respectively, to apoptosis induced by glucose deprivation. Declining Mcl-1 levels and apoptosis induction are inversely correlated to Noxa levels and prevented by readdition of glucose. We propose that the Noxa/Mcl-1 axis is an apoptosis rheostat in dividing cells, in a selective pathway that functions to restrain lymphocyte expansion and can be triggered by glucose deprivation

Language motivation in a reconfigured Europe: access, identity, autonomy

In this paper, I propose that we need to develop an appropriate set of conceptual tools for examining motivational issues pertaining to linguistic diversity, mobility and social integration in a rapidly changing and expanding Europe. I begin by drawing on research that has begun to reframe the concept of integrative motivation in the context of theories of self and identity. Expanding the notion of identity, I discuss the contribution of the Council of Europe's European Language Portfolio in promoting a view of motivation as the development of a plurilingual European identity and the enabling of access and mobility across a multilingual Europe. Next, I critically examine the assumption that the individual pursuit of a plurilingual identity is unproblematic, by highlighting the social context in which motivation and identity are constructed and embedded. To illuminate the role of this social context, I explore three inter-related theoretical frameworks: poststructuralist perspectives on language motivation as 'investment'; sociocultural theory; and theories of autonomy in language education. I conclude with the key message that, as with autonomy, language motivation today has an inescapably political dimension of which we need to take greater account in our research and pedagogical practice

Siblings versus parents and friends:Longitudinal linkages to adolescent externalizing problems

Background: It is well documented that friends’ externalizing problems and negative parent–child interactions predict externalizing problems in adolescence, but relatively little is known about the role of siblings. This four-wave, multi-informant study investigated linkages of siblings’ externalizing problems and sibling–adolescent negative interactions on adolescents’ externalizing problems, while examining and controlling for similar linkages with friends and parents. Methods: Questionnaire data on externalizing problems and negative interactions were annually collected from 497 Dutch adolescents (M = 13.03 years, SD = 0.52, at baseline), as well as their siblings, mothers, fathers, and friends. Results: Cross-lagged panel analyses revealed modest unique longitudinal paths from sibling externalizing problems to adolescent externalizing problems, for male and female adolescents, and for same-sex and mixed-sex sibling dyads, but only from older to younger siblings. Moreover, these paths were above and beyond significant paths from mother–adolescent negative interaction and friend externalizing problems to adolescent externalizing problems, 1 year later. No cross-lagged paths existed between sibling–adolescent negative interaction and adolescent externalizing problems. Conclusions: Taken together, it appears that especially older sibling externalizing problems may be a unique social risk factor for adolescent externalizing problems, equal in strength to significant parents’ and friends’ risk factors

GATA2 haploinsufficient patients lack innate lymphoid cells that arise after hematopoietic cell transplantation.

Innate lymphoid cells (ILC) are important barrier tissue immune regulators. They play a pivotal role in early non-specific protection against infiltrating pathogens, regulation of epithelial integrity, suppression of pro-inflammatory immune responses and shaping the intestinal microbiota. GATA2 haploinsufficiency causes an immune disorder that is characterized by bone marrow failure and (near) absence of monocytes, dendritic cells, B cells and natural killer (NK) cells. T cells develop normally, albeit at lower numbers. Here, we describe the absence of ILCs and their progenitors in blood and bone marrow of two patients with GATA2 haploinsufficiency and show that all subsets of ILCs appear after allogeneic hematopoietic stem cell transplantation, irrespective of the preparative conditioning regimen. Our data indicate that GATA2 is involved in the development of hematopoietic precursor cells (HPC) towards the ILC lineage