Genome-wide association study reveals three susceptibility loci for common migraine in the general population

Migraine is a common, heterogeneous and heritable neurological disorder. Its pathophysiology is incompletely understood, and its genetic influences at the population level are unknown. In a population-based genome-wide analysis including 5,122 migraineurs and 18,108 non-migraineurs, rs2651899 (1p36.32, PRDM16), rs10166942 (2q37.1, TRPM8) and rs11172113 (12q13.3, LRP1) were among the top seven associations (P < 5 × 10(-6)) with migraine. These SNPs were significant in a meta-analysis among three replication cohorts and met genome-wide significance in a meta-analysis combining the discovery and replication cohorts (rs2651899, odds ratio (OR) = 1.11, P = 3.8 × 10(-9); rs10166942, OR = 0.85, P = 5.5 × 10(-12); and rs11172113, OR = 0.90, P = 4.3 × 10(-9)). The associations at rs2651899 and rs10166942 were specific for migraine compared with non-migraine headache. None of the three SNP associations was preferential for migraine with aura or without aura, nor were any associations specific for migraine features. TRPM8 has been the focus of neuropathic pain models, whereas LRP1 modulates neuronal glutamate signaling, plausibly linking both genes to migraine pathophysiology.     

Disruption of mouse Slx4, a regulator of structure-specific nucleases, phenocopies Fanconi anemia

The evolutionarily conserved SLX4 protein, a key regulator of nucleases, is critical for DNA damage response. SLX4 nuclease complexes mediate repair during replication and can also resolve Holliday junctions formed during homologous recombination. Here we describe the phenotype of the Btbd12 knockout mouse, the mouse ortholog of SLX4, which recapitulates many key features of the human genetic illness Fanconi anemia. Btbd12-deficient animals are born at sub-Mendelian ratios, have greatly reduced fertility, are developmentally compromised and are prone to blood cytopenias. Btbd12(-/-) cells prematurely senesce, spontaneously accumulate damaged chromosomes and are particularly sensitive to DNA crosslinking agents. Genetic complementation reveals a crucial requirement for Btbd12 (also known as Slx4) to interact with the structure-specific endonuclease Xpf-Ercc1 to promote crosslink repair. The Btbd12 knockout mouse therefore establishes a disease model for Fanconi anemia and genetically links a regulator of nuclease incision complexes to the Fanconi anemia DNA crosslink repair pathway.     

Maturation trends indicative of rapid evolution preceded the collapse of northern cod

Northern cod, comprising populations of Atlantic cod (Gadus morhua) off southern Labrador and eastern Newfoundland, supported major fisheries for hundreds of years. But in the late 1980s and early 1990s, northern cod underwent one of the worst collapses in the history of fisheries. The Canadian government closed the directed fishing for northern cod in July 1992, but even after a decade-long offshore moratorium, population sizes remain historically low. Here we show that, up until the moratorium, the life history of northern cod continually shifted towards maturation at earlier ages and smaller sizes. Because confounding effects of mortality changes and growth-mediated phenotypic plasticity are accounted for in our analyses, this finding strongly suggests fisheries-induced evolution of maturation patterns in the direction predicted by theory. We propose that fisheries managers could use the method described here as a tool to provide warning signals about changes in life history before more overt evidence of population decline becomes manifest.     

Performance analysis of optimal channel estimation and multiuser detection in a randomly-spread CDMA channel

<正> This paper analyzes performance of optimal channel estimation and multiuser detection(MUD) in a block-fading code-division multiple-access (CDMA) channel on the assumptions of randomspreading and large-system limit,by using the replica method developed in statistical mechanics.The authors find that the asymptotic spectral efficiency of the linear minimum mean-squared error(LMMSE) MUD which was proposed and analyzed by Evans and Tse in 2000 is indistinguishable fromthat of the optimal MUD for small system loads.Our results imply that performance of MUD scarcelyimproves even if one spends more computational cost than that of the LMMSE MUD,i.e.,at most thecube of the number of users,on the above-described conditions.     

The gene disrupted in Marinesco-Sjögren syndrome encodes SIL1, an HSPA5 cochaperone

We identified the gene underlying Marinesco-Sj?gren syndrome, which is characterized by cerebellar ataxia, progressive myopathy and cataracts. We identified four disease-associated, predicted loss-of-function mutations in SIL1, which encodes a nucleotide exchange factor for the heat-shock protein 70 (HSP70) chaperone HSPA5. These data, together with the similar spatial and temporal patterns of tissue expression of Sil1 and Hspa5, suggest that disturbed SIL1-HSPA5 interaction and protein folding is the primary pathology in Marinesco-Sj?gren syndrome.     

Contemporary fisherian life-history evolution in small salmonid populations

The relative importance of natural selection and random drift in phenotypic evolution has been discussed since the introduction of the first population genetic models. The empirical evidence used to evaluate the evolutionary theories of Fisher and Wright remains obscure because formal tests for neutral divergence or sensitive attempts to separate the effects of selection and drift are scarce, subject to error, and have not been interpreted in the light of well-known population demography. We combined quantitative genetic and microsatellite DNA analyses to investigate the determinants of contemporary life-history evolution in isolated populations of grayling (Thymallus thymallus, Salmonidae) that originated from a common source 80-120 years ago. Here we show that natural selection was the dominant diversifying agent in the evolution of the quantitative traits. However, the populations were founded by a small number of individuals, exhibit very low microsatellite-based effective sizes and show genetic imprints of severe 'bottlenecks'; which are conditions often suggested to constrain selection and favour drift. This study demonstrates a very clear case of fisherian evolution in small natural populations across a contemporary timescale.     

Enrichment of ligands with molecular dockings and subsequent characterization for human alcohol dehydrogenase 3

Alcohol dehydrogenase 3 (ADH3) has been assigned a role in nitric oxide homeostasis due to its function as an S-nitrosoglutathione reductase. As altered S-nitrosoglutathione levels are often associated with disease, compounds that modulate ADH3 activity might be of therapeutic interest. We performed a virtual screening with molecular dockings of more than 40,000 compounds into the active site of human ADH3. A novel knowledge-based scoring method was used to rank compounds, and several compounds that were not known to interact with ADH3 were tested in vitro. Two of these showed substrate activity (9-decen-1-ol and dodecyltetraglycol), where calculated binding scoring energies correlated well with the logarithm of the k _cat/K _m values for the substrates. Two compounds showed inhibition capacity (deoxycholic acid and doxorubicin), and with these data three different lines for specific inhibitors for ADH3 are suggested: fatty acids, glutathione analogs, and cholic acids.     

Mutations in DMRT3 affect locomotion in horses and spinal circuit function in mice

Locomotion in mammals relies on a central pattern-generating circuitry of spinal interneurons established during development that coordinates limb movement. These networks produce left-right alternation of limbs as well as coordinated activation of flexor and extensor muscles. Here we show that a premature stop codon in the DMRT3 gene has a major effect on the pattern of locomotion in horses. The mutation is permissive for the ability to perform alternate gaits and has a favourable effect on harness racing performance. Examination of wild-type and Dmrt3-null mice demonstrates that Dmrt3 is expressed in the dI6 subdivision of spinal cord neurons, takes part in neuronal specification within this subdivision, and is critical for the normal development of a coordinated locomotor network controlling limb movements. Our discovery positions Dmrt3 in a pivotal role for configuring the spinal circuits controlling stride in vertebrates. The DMRT3 mutation has had a major effect on the diversification of the domestic horse, as the altered gait characteristics of a number of breeds apparently require this mutation.     

The contribution of Shaker K+ channels to the information capacity of Drosophila photoreceptors

An array of rapidly inactivating voltage-gated K+ channels is distributed throughout the nervous systems of vertebrates and invertebrates. Although these channels are thought to regulate the excitability of neurons by attenuating voltage signals, their specific functions are often poorly understood. We studied the role of the prototypical inactivating K+ conductance, Shaker, in Drosophila photoreceptors by recording intracellularly from wild-type and Shaker mutant photoreceptors. Here we show that loss of the Shaker K+ conductance produces a marked reduction in the signal-to-noise ratio of photoreceptors, generating a 50% decrease in the information capacity of these cells in fully light-adapted conditions. By combining experiments with modelling, we show that the inactivation of Shaker K+ channels amplifies voltage signals and enables photoreceptors to use their voltage range more effectively. Loss of the Shaker conductance attenuated the voltage signal and induced a compensatory decrease in impedance. Our results demonstrate the importance of the Shaker K+ conductance for neural coding precision and as a mechanism for selectively amplifying graded signals in neurons, and highlight the effect of compensatory mechanisms on neuronal information processing.