University of Sheffield

About: University of Sheffield is a education organization based out in Sheffield, United Kingdom. It is known for research contribution in the topics: Population & Context (language use). The organization has 41675 authors who have published 102908 publications receiving 3946383 citations. The organization is also known as: Sheffield University & shef.ac.uk.

Molecular pathways of motor neuron injury in amyotrophic lateral sclerosis

Abstract: Amyotrophic lateral sclerosis (ALS) is a genetically diverse disease. At least 15 ALS-associated gene loci have so far been identified, and the causative gene is known in approximately 30% of familial ALS cases. Less is known about the factors underlying the sporadic form of the disease. The molecular mechanisms of motor neuron degeneration are best understood in the subtype of disease caused by mutations in superoxide dismutase 1, with a current consensus that motor neuron injury is caused by a complex interplay between multiple pathogenic processes. A key recent finding is that mutated TAR DNA-binding protein 43 is a major constituent of the ubiquitinated protein inclusions in ALS, providing a possible link between the genetic mutation and the cellular pathology. New insights have also indicated the importance of dysregulated glial cell-motor neuron crosstalk, and have highlighted the vulnerability of the distal axonal compartment early in the disease course. In addition, recent studies have suggested that disordered RNA processing is likely to represent a major contributing factor to motor neuron disease. Ongoing research on the cellular pathways highlighted in this Review is predicted to open the door to new therapeutic interventions to slow disease progression in ALS.

Inhibition of human Chk1 causes increased initiation of DNA replication, phosphorylation of ATR targets, and DNA breakage.

Abstract: Human checkpoint kinase 1 (Chk1) is an essential kinase required to preserve genome stability. Here, we show that Chk1 inhibition by two distinct drugs, UCN-01 and CEP-3891, or by Chk1 small interfering RNA (siRNA) leads to phosphorylation of ATR targets. Chk1-inhibition triggered rapid, pan-nuclear phosphorylation of histone H2AX, p53, Smc1, replication protein A, and Chk1 itself in human S-phase cells. These phosphorylations were inhibited by ATR siRNA and caffeine, but they occurred independently of ATM. Chk1 inhibition also caused an increased initiation of DNA replication, which was accompanied by increased amounts of nonextractable RPA protein, formation of single-stranded DNA, and induction of DNA strand breaks. Moreover, these responses were prevented by siRNA-mediated downregulation of Cdk2 or the replication initiation protein Cdc45, or by addition of the CDK inhibitor roscovitine. We propose that Chk1 is required during normal S phase to avoid aberrantly increased initiation of DNA replication, thereby protecting against DNA breakage. These results may help explain why Chk1 is an essential kinase and should be taken into account when drugs to inhibit this kinase are considered for use in cancer treatment.

Future work design research and practice: Towards an elaborated model of work design

Abstract: Developments in work design theory have not kept pace with the changes occurring in the organizational landscape. We propose a theoretical framework that specifies five categories of work design variables that span individual, group and organizational levels of analysis. Specifically, we propose an elaborated model of work design that includes: systematic consideration of antecedents of work characteristics; expansion of the traditional range of work characteristics to include aspects salient to the modern context; extension of the range of outcome variables beyond the existing narrow focus on affective reactions; analysis of the mechanisms, or processes, that explain why work characteristics lead to particular outcomes; and consideration of contingencies that moderate the effects of work characteristics. We argue that the particular choice of work design variables should be guided by theory and an analysis of the organizational context.

Genital damage, kicking and early death

Abstract: The battle of the sexes takes a sinister turn in the bean weevil. Because the costs and benefits of polygamy differ for males and females, copulation is not always a cooperative venture between the sexes1. Sperm competition2 can build on this asymmetry, producing male traits that harm females3,4 thereby generating coevolutionary arms races between the sexes5. We have found that the male genitalia of the bean weevil Callosobruchus maculatus damage the female genitalia, and that females act to reduce the extent of this damage. We propose that these functionally diametric sexual traits form the basis of reproductive conflict.

Increasing human dominance of tropical forests.

Abstract: Tropical forests house over half of Earth’s biodiversity and are an important influence on the climate system. These forests are experiencing escalating human influence, altering their health and the provision of important ecosystem functions and services. Impacts started with hunting and millennia-old megafaunal extinctions (phase I), continuing via low-intensity shifting cultivation (phase II), to today’s global integration, dominated by intensive permanent agriculture, industrial logging, and attendant fires and fragmentation (phase III). Such ongoing pressures, together with an intensification of global environmental change, may severely degrade forests in the future (phase IV, global simplification) unless new “development without destruction” pathways are established alongside climate change–resilient landscape designs.