Proceedings of the National Academy of Sciences of the United States of America
-
Proc. Natl. Acad. Sci. U.S.A. · May 2009
Analysis of genomic diversity in Mexican Mestizo populations to develop genomic medicine in Mexico.
Mexico is developing the basis for genomic medicine to improve healthcare of its population. The extensive study of genetic diversity and linkage disequilibrium structure of different populations has made it possible to develop tagging and imputation strategies to comprehensively analyze common genetic variation in association studies of complex diseases. We assessed the benefit of a Mexican haplotype map to improve identification of genes related to common diseases in the Mexican population. ⋯ Our results provide evidence of genetic differences between Mexican subpopulations that should be considered in the design and analysis of association studies of complex diseases. In addition, these results support the notion that a haplotype map of the Mexican Mestizo population can reduce the number of tag SNPs required to characterize common genetic variation in this population. This is one of the first genomewide genotyping efforts of a recently admixed population in Latin America.
-
Proc. Natl. Acad. Sci. U.S.A. · May 2009
Suppressed Ca2+/CaM/CaMKII-dependent K(ATP) channel activity in primary afferent neurons mediates hyperalgesia after axotomy.
Painful axotomy decreases K(ATP) channel current (IK(ATP)) in primary afferent neurons. Because cytosolic Ca(2+) signaling is depressed in injured dorsal root ganglia (DRG) neurons, we investigated whether Ca(2+)-calmodulin (CaM)-Ca(2+)/CaM-dependent kinase II (CaMKII) regulates IK(ATP) in large DRG neurons. Immunohistochemistry identified the presence of K(ATP) channel subunits SUR1, SUR2, and Kir6.2 but not Kir6.1, and pCaMKII in neurofilament 200-positive DRG somata. ⋯ Axotomized neurons from rats made hyperalgesic by SNL lost sensitivity to the myristoylated form of autocamtide-2-related inhibitory peptide (AIPm), a pseudosubstrate blocker of CaMKII, whereas axotomized neurons from SNL animals that failed to develop hyperalgesia showed normal IK(ATP) inhibition by AIPm. AIPm also depolarized RMP in control neurons via K(ATP) channel inhibition. Unitary current conductance and sensitivity of K(ATP) channels to cytosolic ATP and ligands were preserved even after painful nerve injury, thus providing opportunities for selective therapeutic targeting against neuropathic pain.
-
Proc. Natl. Acad. Sci. U.S.A. · May 2009
Experience sampling during fMRI reveals default network and executive system contributions to mind wandering.
Although mind wandering occupies a large proportion of our waking life, its neural basis and relation to ongoing behavior remain controversial. We report an fMRI study that used experience sampling to provide an online measure of mind wandering during a concurrent task. Analyses focused on the interval of time immediately preceding experience sampling probes demonstrate activation of default network regions during mind wandering, a finding consistent with theoretical accounts of default network functions. ⋯ Finally, neural recruitment in both default and executive network regions was strongest when subjects were unaware of their own mind wandering, suggesting that mind wandering is most pronounced when it lacks meta-awareness. The observed parallel recruitment of executive and default network regions--two brain systems that so far have been assumed to work in opposition--suggests that mind wandering may evoke a unique mental state that may allow otherwise opposing networks to work in cooperation. The ability of this study to reveal a number of crucial aspects of the neural recruitment associated with mind wandering underscores the value of combining subjective self-reports with online measures of brain function for advancing our understanding of the neurophenomenology of subjective experience.
-
Proc. Natl. Acad. Sci. U.S.A. · May 2009
IFN-gamma receptor signaling mediates spinal microglia activation driving neuropathic pain.
Neuropathic pain, a highly debilitating pain condition that commonly occurs after nerve damage, is a reflection of the aberrant excitability of dorsal horn neurons. This pathologically altered neurotransmission requires a communication with spinal microglia activated by nerve injury. However, how normal resting microglia become activated remains unknown. ⋯ Conversely, ablating IFN-gammaR severely impairs nerve injury-evoked microglia activation and tactile allodynia without affecting microglia in the contralateral dorsal horn or basal pain sensitivity. We also find that IFN-gamma-stimulated spinal microglia show up-regulation of Lyn tyrosine kinase and purinergic P2X(4) receptor, crucial events for neuropathic pain, and genetic approaches provide evidence linking these events to IFN-gammaR-dependent microglial and behavioral alterations. These results suggest that IFN-gammaR is a key element in the molecular machinery through which resting spinal microglia transform into an activated state that drives neuropathic pain.
-
Proc. Natl. Acad. Sci. U.S.A. · May 2009
Molecular dissection of Alzheimer's disease neuropathology by depletion of serum amyloid P component.
New therapeutic approaches in Alzheimer's disease are urgently needed. The normal plasma protein, serum amyloid P component (SAP), is always present in cerebrospinal fluid (CSF) and in the pathognomonic lesions of Alzheimer's disease, cerebrovascular and intracerebral Abeta amyloid plaques and neurofibrillary tangles, as a result of its binding to amyloid fibrils and to paired helical filaments, respectively. SAP itself may also be directly neurocytotoxic. ⋯ We demonstrate that SAP depletion in vivo is caused by CPHPC cross-linking pairs of SAP molecules in solution to form complexes that are immediately cleared from the plasma. We have also solved the structure of SAP complexed with phosphothreonine, its likely ligand on hyperphosphorylated tau protein. These results support further clinical study of SAP depletion in Alzheimer's disease and potentially other neurodegenerative diseases.