Macrophage migration inhibitory factor stimulates AMP-activated protein kinase in the ischaemic heart

Understanding cellular response to environmental stress has broad implications for human disease. AMP-activated protein kinase (AMPK) orchestrates the regulation of energy-generating and -consuming pathways, and protects the heart against ischaemic injury and apoptosis. A role for circulating hormones such as adiponectin and leptin in the activation of AMPK has received recent attention. Whether local autocrine and paracrine factors within target organs such as the heart modulate AMPK is unknown. Here we show that macrophage migration inhibitory factor (MIF), an upstream regulator of inflammation, is released in the ischaemic heart, where it stimulates AMPK activation through CD74, promotes glucose uptake and protects the heart during ischaemia-reperfusion injury. Germline deletion of the Mif gene impairs ischaemic AMPK signalling in the mouse heart. Human fibroblasts with a low-activity MIF promoter polymorphism have diminished MIF release and AMPK activation during hypoxia. Thus, MIF modulates the activation of the cardioprotective AMPK pathway during ischaemia, functionally linking inflammation and metabolism in the heart. We anticipate that genetic variation in MIF expression may impact on the response of the human heart to ischaemia by the AMPK pathway, and that diagnostic MIF genotyping might predict risk in patients with coronary artery disease.     

A lysosomal enigma CLN5 and its significance in understanding neuronal ceroid lipofuscinosis

Cellular and Molecular Life Sciences - Neuronal Ceroid Lipofuscinosis (NCL), also known as Batten disease, is an incurable childhood brain disease. The thirteen forms of NCL are caused by mutations...     

A whole-genome admixture scan finds a candidate locus for multiple sclerosis susceptibility

Multiple sclerosis is a common disease with proven heritability, but, despite large-scale attempts, no underlying risk genes have been identified. Traditional linkage scans have so far identified only one risk haplotype for multiple sclerosis (at HLA on chromosome 6), which explains only a fraction of the increased risk to siblings. Association scans such as admixture mapping have much more power, in principle, to find the weak factors that must explain most of the disease risk. We describe here the first high-powered admixture scan, focusing on 605 African American cases and 1,043 African American controls, and report a locus on chromosome 1 that is significantly associated with multiple sclerosis.     

Taphonomy and significance of Jefferson's ground sloth (Xenarthra: Megalonychidae) from Utah

While a variety of mammalian megafauna have been recovered from sediments associated with Lake Bonneville, Utah, sloths have been notably rare. Three species of ground sloth, Megalonyx jeffersonii, Paramylodon harlani, and Nothrotheriops shastensis , are known from the western United States during the Pleistocene. Yet all 3 are rare in the Great Basin, and the few existing records are from localities on the basin margin. The recent discovery of a partial skeleton of Megalonyx jeffersonii at Point-of-the-Mountain, Salt Lake County, Utah, fits this pattern and adds to our understanding of the distribution and ecology of this extinct species. Its occurrence in Lake Bonneville shoreline deposits permits a reasonable age determination of between 22 and 13 ka.     

Species-specific responses of Late Quaternary megafauna to climate and humans

Despite decades of research, the roles of climate and humans in driving the dramatic extinctions of large-bodied mammals during the Late Quaternary period remain contentious. Here we use ancient DNA, species distribution models and the human fossil record to elucidate how climate and humans shaped the demographic history of woolly rhinoceros, woolly mammoth, wild horse, reindeer, bison and musk ox. We show that climate has been a major driver of population change over the past 50,000 years. However, each species responds differently to the effects of climatic shifts, habitat redistribution and human encroachment. Although climate change alone can explain the extinction of some species, such as Eurasian musk ox and woolly rhinoceros, a combination of climatic and anthropogenic effects appears to be responsible for the extinction of others, including Eurasian steppe bison and wild horse. We find no genetic signature or any distinctive range dynamics distinguishing extinct from surviving species, emphasizing the challenges associated with predicting future responses of extant mammals to climate and human-mediated habitat change.     

Electrostatic interactions in the assembly of haemoglobin

Haemoglobin is the prototype of an allosteric protein in which cooperative behaviour depends on interaction between unlike subunits. Here we present haematological and biochemical evidence that electrostatic interactions are an important determinant of haemoglobin assembly. Individuals heterozygous for positively charged beta-globin variants have a significantly lower proportion of abnormal haemoglobin than those with negatively charged variants. Moreover, these differences become more pronounced when alpha-thalassaemia is also present. Kinetic experiments using isolated chains indicate that the rate of assembly of the heterotetramer is influenced by alterations in surface charge. A simple electrostatic model is proposed in an attempt to explain these haematological and experimental findings.