A genome-wide study replicates linkage of 3p22-24 to extreme longevity in humans and identifies possible additional loci

Journal ArticleBackground: Although there is abundant evidence that human longevity is heritable, efforts to map loci responsible for variation in human lifespan have had limited success. Methodology/Principal Findings: We identified individuals from a large multigenerational population database (the Utah Population Database) who exhibited high levels of both familial longevity and individual longevity. This selection identified 325 related ‘‘affected individuals'', defined as those in the top quartile for both excess longevity (EL = observed lifespan - expected lifespan) and familial excess longevity (FEL = weighted average EL across all relatives). A whole-genome scan for genetic linkage was performed on this sample using a panel of 1100 microsatellite markers. A strongly suggestive peak (Z = 4.2, Monte Carlo-adjusted p-value 0.09) was observed in the vicinity of D3S3547 on chromosome 3p24.1, at a point nearly identical to that reported recently by an independent team of researchers from Harvard Medical School (HMS) [1]. Meta-analysis of linkage scores on 3p from the two studies produced a minimum nominal p-value of 1.00561029 at 55 cM. Other potentially noteworthy peaks in our data occur on 18q23-24, 8q23, and 17q21. Meta-analysis results from combined UPDB and HMS data yielded additional support, but not formal replication, for linkage on 8q, 9q, and 17q. Conclusions/Significance: Corroboration of the linkage of exceptional longevity to 3p22-24 greatly strengthens the case that genes in this region affect variation in longevity and suggest, therefore, an important role in the regulation of human lifespan. Future efforts should include intensive study of the 3p22-24 region

Mitochondrial genomic analysis of late onset alzheimers disease reveals protective haplogroups H6A1A/H6A1B: the Cache County study on memory in aging

pre-printBackground: Alzheimer's disease (AD) is the most common cause of dementia and AD risk clusters within families. Part of the familial aggregation of AD is accounted for by excess maternal vs. paternal inheritance, a pattern consistent with mitochondrial inheritance. The role of specific mitochondrial DNA (mtDNA) variants and haplogroups in AD risk is uncertain. Methodology/Principal Findings: We determined the complete mitochondrial genome sequence of 1007 participants in the Cache County Study on Memory in Aging, a population-based prospective cohort study of dementia in northern Utah. AD diagnoses were made with a multi-stage protocol that included clinical examination and review by a panel of clinical experts. We used TreeScanning, a statistically robust approach based on haplotype networks, to analyze the mtDNA sequence data. Participants with major mitochondrial haplotypes H6A1A and H6A1B showed a reduced risk of AD (p = 0.017, corrected for multiple comparisons). The protective haplotypes were defined by three variants: m.3915G.A, m.4727A.G, and m.9380G.A. These three variants characterize two different major haplogroups. Together m.4727A.G and m.9380G.A define H6A1, and it has been suggested m.3915G.A defines H6A. Additional variants differentiate H6A1A and H6A1B; however, none of these variants had a significant relationship with AD case-control status. Conclusions/Significance: Our findings provide evidence of a reduced risk of AD for individuals with mtDNA haplotypes H6A1A and H6A1B. These findings are the results of the largest study to date with complete mtDNA genome sequence data, yet the functional significance of the associated haplotypes remains unknown and replication in others studies is necessary

Familial Aggregation of Survival and Late Female Reproduction

Abstract not availabl

Triphasic waveforms are superior to biphasic waveforms for transthoracic defibrillation Experimental studies

AbstractObjectivesOur objective was to evaluate the efficacy of triphasic waveforms for transthoracic defibrillation in a swine model.BackgroundTriphasic shocks have been found to cause less post-shock dysfunction than biphasic shocks in chick embryo studies.MethodsAfter 30 s of electrically induced ventricular fibrillation (VF), each pig in part I (n = 32) received truncated exponential biphasic (7.2/7.2 ms) and triphasic (4.8/4.8/4.8 ms) transthoracic shocks. Each pig in part II (n = 14) received biphasic (5/5 ms) and triphasic shocks (5/5/5 ms). Three selected energy levels (50, 100, and 150 J) were tested for parts I and II. Pigs in part III (n = 13) received biphasic (5/5 ms) and triphasic (5/5/5 ms) shocks at a higher energy (200 and 300 J). Although the individual pulse durations of these shocks were equal, the energy of each pulse varied. Nine pigs in part I also received shocks where each individual pulse contained equal energy but was of a different duration (biphasic 3.3/11.1 ms; triphasic 2.0/3.2/9.2 ms).ResultsTriphasic shocks of equal duration pulses achieved higher success than biphasic shocks at delivered low energies: <40 J: 38 ± 5% triphasic vs. 19 ± 4% biphasic (p < 0.01); 40 to <50 J: 66 ± 7% vs. 42 ± 7% (p < 0.01); and 50 to <65 J: 78 ± 4% vs. 54 ± 5% (p < 0.05). Shocks of equal energy but different duration pulses achieved relatively poor success for both triphasic and biphasic waveforms. Shock-induced ventricular tachycardia (VT) and asystole occurred less often after triphasic shocks.ConclusionsTriphasic transthoracic shocks composed of equal duration pulses were superior to biphasic shocks for VF termination at low energies and caused less VT and asystole

Imaging Myosin-X at the Single-Molecule Level Reveals a Novel Form of Motility in Filopodia

Although many proteins, receptors, and viruses are transported rearward along filopodia by retrograde actin flow[1-3], it is less clear how molecules move forward in filopodia. Myosin-X (Myo10) is an actin-based motor hypothesized to use its motor activity to move forward along actin filaments to the tips of filopodia[4]. Here we use a sensitive total internal reflection fluorescence (TIRF) microscopy system to directly visualize the movements of GFP-Myo10. This reveals a novel form of motility at or near the single-molecule level in living cells wherein extremely faint particles of Myo10 move in a rapid and directed fashion towards the filopodial tip. These fast forward movements occur at ∼600 nm/s over distances of up to ∼10 μm and require Myo10 motor activity and actin filaments. As expected for imaging at the single-molecule level, the faint particles of GFP-Myo10 are diffraction-limited, have an intensity range similar to single GFP molecules, and exhibit stepwise bleaching. Faint particles of GFP-Myo5a can also move towards the filopodial tip, but at a slower characteristic velocity of ∼250 nm/s. Similar movements were not detected with GFP-Myo1a, indicating that not all myosins are capable of intrafilopodial motility. These data indicate the existence of a novel system of long-range transport based on the rapid movement of myosin molecules along filopodial actin filaments

Design considerations in a sib-pair study of linkage for susceptibility loci in cancer

<p>Abstract</p> <p>Background</p> <p>Modern approaches to identifying new genes associated with disease allow very fine analysis of associaton and can be performed in population based case-control studies. However, the sibpair design is still valuable because it requires few assumptions other than acceptably high penetrance to identify genetic loci.</p> <p>Methods</p> <p>We conducted simulation studies to assess the impact of design factors on relative efficiency for a linkage study of colorectal cancer. We considered two test statistics, one comparing the mean IBD probability in affected pairs to its null value of 0.5, and one comparing the mean IBD probabilities between affected and discordant pairs. We varied numbers of parents available, numbers of affected and unaffected siblings, reconstructing the genotype of an unavailable affected sibling by a spouse and offspring, and elimination of sibships where the proband carries a mutation at another locus.</p> <p>Results</p> <p>Power and efficiency were most affected by the number of affected sibs, the number of sib pairs genotyped, and the risk attributable to linked and unlinked loci. Genotyping unaffected siblings added little power for low penetrance models, but improved validity of tests when there was genetic heterogeneity and for multipoint testing. The efficiency of the concordant-only test was nearly always better than the concordant-discordant test. Replacement of an unavailable affected sibling by a spouse and offspring recovered some linkage information, particularly if several offspring were available. In multipoint analysis, the concordant-only test was showed a small anticonservative bias at 5 cM, while the multipoint concordant-discordant test was generally the most powerful test, and was not biased away from the null at 5 cM.</p> <p>Conclusion</p> <p>Genotyping parents and unaffected siblings is useful for detecting genotyping errors and if allele frequencies are uncertain. If adequate allele frequency data are available, we suggest a single-point affecteds-only analysis for an initial scan, followed by a multipoint analysis of affected and unaffected members of all available sibships with additional markers around initial hits.</p

Evidence from MESSENGER for sulfur‐ and carbon‐driven explosive volcanism on Mercury

Targeted MErcury Surface, Space ENvironment, GEochemistry, and Ranging (MESSENGER) X‐Ray Spectrometer measurements of Mercury's largest identified pyroclastic deposit are combined with neutron and reflectance spectroscopy data to constrain the composition of volatiles involved in the eruption that emplaced the pyroclastic material. The deposit, northeast of the Rachmaninoff basin, is depleted in S (relative to Ca and Si) and C, compared with the rest of Mercury's surface. Spectral reflectance measurements of the deposit indicate relatively high overall reflectance and an oxygen‐metal charge transfer (OMCT) absorption band at ultraviolet wavelengths. These results are consistent with oxidation of graphite and sulfides during magma ascent, via reaction with oxides in the magma or assimilated country rock, and the formation of S‐ and C‐bearing volatile species. Consumption of graphite during oxidation could account for the elevated reflectance of the pyroclastic material, and the strength of the OMCT band is consistent with ~0.03–0.1 wt % FeO in the deposit