Temporary derailment or the end of the line? Managers coping with unemployment at 50

Based on fieldwork conducted at the outset of the 2008 economic downturn, this paper examines the experiences of a group of unemployed managers and professionals in their fifties. Following a review of existing literature, the authors use a narrative methodology to explore how these people incorporate the experience of job loss into their self-images and identities. They identify certain core similarities in the experiences of unemployed professionals and then discern three narrative strategies through which unemployed professionals tried to make sense of their dismissal and sustain their sense of selfhood. The term ‘narrative coping’ is proposed as a way of describing each unemployed professional’s struggle to construct a story that offers both meaning and consolation. The study reveals that individuals expressing the most profound despair (those for whom job loss was the ‘end of the line’) were those whose stories had achieved ‘closure’. By contrast, most of those who maintained more open-ended narratives were better able to contain their emotions, either by holding on to the belief that unemployment was a temporary career aberration or by abandoning the idea that life is the same as career and by moving on to a new stage of experimentation and bricolage akin to an identity moratorium

Discovery of (<i>S</i>)‑1-(1-(4-Chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl‑1<i>H</i>‑pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1<i>H</i>)‑one (GDC-0994), an Extracellular Signal-Regulated Kinase 1/2 (ERK1/2) Inhibitor in Early Clinical Development

The extracellular signal-regulated kinases ERK1/2 represent an essential node within the RAS/RAF/MEK/ERK signaling cascade that is commonly activated by oncogenic mutations in BRAF or RAS or by upstream oncogenic signaling. While targeting upstream nodes with RAF and MEK inhibitors has proven effective clinically, resistance frequently develops through reactivation of the pathway. Simultaneous targeting of multiple nodes in the pathway, such as MEK and ERK, offers the prospect of enhanced efficacy as well as reduced potential for acquired resistance. Described herein is the discovery and characterization of GDC-0994 (<b>22</b>), an orally bioavailable small molecule inhibitor selective for ERK kinase activity

Premutation CGG-repeat expansion of the Fmr1 gene impairs mouse neocortical development

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late adult-onset neurodegenerative disorder caused by a premutation CGG-trinucleotide repeat expansion (55–200 CGG repeats) within the 5′-untranslated region of the FMR1 gene. Although FXTAS generally affects premutation carriers over 50 years of age, cognitive and psychological symptoms can appear in carriers during childhood, suggesting that the FMR1 premutation affects brain function early in life. Recent work with cultured hippocampal neurons from a premutation (Fmr1 CGG knock-in) mouse model revealed impaired development of early postnatal neurons, consistent with the developmental clinical involvement of premutation carriers. In the current work, we show that the presence of premutation CGG-repeat expansions in the mouse Fmr1 gene alters embryonic neocortical development. Specifically, embryonic premutation mice display migration defects in the neocortex and altered expression of neuronal lineage markers. The current data demonstrate that premutation alleles of the Fmr1 gene are associated with defects in developmental programs operating during prenatal stages of brain formation and provide further evidence that the FMR1 premutation has a neurodevelopmental component