Self-oligomerization regulates stability of survival motor neuron protein isoforms by sequestering an SCF^Slmb degron

Spinal muscular atrophy (SMA) is caused by homozygous mutations in human SMN1. Expression of a duplicate gene (SMN2) primarily results in skipping of exon 7 and production of an unstable protein isoform, SMNΔ7. Although SMN2 exon skipping is the principal contributor to SMA severity, mechanisms governing stability of survival motor neuron (SMN) isoforms are poorly understood. We used a Drosophila model system and label-free proteomics to identify the SCFSlmb ubiquitin E3 ligase complex as a novel SMN binding partner. SCFSlmb interacts with a phosphor degron embedded within the human and fruitfly SMN YG-box oligomerization domains. Substitution of a conserved serine (S270A) interferes with SCFSlmb binding and stabilizes SMNΔ7. SMA-causing missense mutations that block multimerization of full-length SMN are also stabilized in the degron mutant background. Overexpression of SMNΔ7S270A, but not wild-type (WT) SMNΔ7, provides a protective effect in SMA model mice and human motor neuron cell culture systems. Our findings support a model wherein the degron is exposed when SMN is monomeric and sequestered when SMN forms higher-order multimers

Separation logic and concurrency

Concurrent separation logic is a development of Hoare logic adapted to deal with pointers and concurrency. Since its inception, it has been enhanced with a treatment of permissions to enable sharing of data between threads, and a treatment of variables as resource alongside heap cells as resource. An introduction to the logic is given with several examples of proofs, culminating in a treatment of Simpson’s 4-slot algorithm, an instance of racy non-blocking concurrency

Inter-process buffers in separation logic with rely-guarantee

Separation logic allows simple proofs of concurrent algorithms which use blocking mechanisms such as semaphores. It can even deal with non-blocking algorithms. With the addition of mechanisms borrowed from rely-guarantee, we can make reasonably simple proofs of some simple non-blocking algorithms. We show that it extends to proofs of some intricate algorithms, including Simpson’s famous asynchronous four-slot buffer and Harris’s novel three-slot algorithm, in a manner that is arguably simpler than earlier treatments, though we cannot claim that we have yet found proofs that are as simple as we would wish. Our example proofs show functional correctness but do not deal with questions of liveness

The evolving model of capitalism in Ireland: an insight into enterprise development and policy

Contemporary capitalism in Ireland took off in the late 1950s and affirmed itself as an inward investment-focused model of development. With enterprise development at the core of the policy (as a way of developing the economy and society and ending emigration), all other policy domains - financial, governance, industrial relations, welfare and education - became subservient to the industrialization-by-invitation' strategy. This article examines and characterizes the Irish model of development, using the lens of the varieties of capitalism literature (VoC) as a starting point. The article also examines whether a stage theory of capitalism perspective can capture changes which the VoC perspective might obscure. The collapse of the Irish banking system since 2008 and the subsequent recession raises major challenges for Ireland's variety of capitalism and may represent a critical juncture