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

The water vapour radiometer of Paranal: homogeneity of precipitable water vapour from two years of operations

A Low Humidity and Temperature Profiling (LHATPRO) microwave radiometer, manufactured by Radiometer Physics GmbH (RPG),is used to monitor sky conditions over ESO's Paranal observatory in support of VLT science operations. The unit measures several channels across the strong water vapour emission line at 183 GHz, necessary for resolving the low levels of precipitable water vapour (PWV) that are prevalent on Paranal (median similar to 2.4 mm). The instrument consists of a humidity profiler (183-191 GHz),a temperature profiler (51-58 GHz),and an infrared camera (similar to 10 mu m) for cloud detection. We present a statistical analysis of the homogeneity of all-sky PWV using 24 months of PWV observations. The question we tried to address was whether PWV is homogeneous enough across the sky such that service mode observations with the VLT can routinely be conducted with a user-provided constraint for PWV measured at zenith. We find the PWV over Paranal to be remarkably homogeneous across the sky down to 27.5 degrees elevation with a median variation of 0.07 mm (rms). The homogeneity is a function of the absolute PWV but the relative variation is fairly constant at 2 to 3% (rms). Such variations will not be a significant issue for analysis of astronomical data. Users at ESO can specify PWV - measured at zenith - as an ambient constraint in service mode to enable, for instance, very demanding observations in the infrared. We conclude that in general it will not be necessary to add another observing constraint for PWV homogeneity to ensure integrity of observations. For demanding observations requiring very low PWV, where the relative variation is higher, the optimum support could be provided by observing with the LHATPRO in the same line-of-sight simultaneously. Such a mode of operations has already been tested but will have to be justified in terms of scientific gain before implementation can be considered. We plan to extend our analysis of PWV variations covering a larger parameters space for temporal and spatial resolution in the future. Also for climate studies such data sets will be relevant

Myosin-X: a MyTH-FERM myosin at the tips of filopodia

Myosin-X (Myo10) is an unconventional myosin with MyTH4-FERM domains that is best known for its striking localization to the tips of filopodia and its ability to induce filopodia. Although the head domain of Myo10 enables it to function as an actin-based motor, its tail contains binding sites for several molecules with central roles in cell biology, including phosphatidylinositol (3,4,5)-trisphosphate, microtubules and integrins. Myo10 also undergoes fascinating long-range movements within filopodia, which appear to represent a newly recognized system of transport. Myo10 is also unusual in that it is a myosin with important roles in the spindle, a microtubule-based structure. Exciting new studies have begun to reveal the structure and single-molecule properties of this intriguing myosin, as well as its mechanisms of regulation and induction of filopodia. At the cellular and organismal level, growing evidence demonstrates that Myo10 has crucial functions in numerous processes ranging from invadopodia formation to cell migration

Familial Aggregation of Survival and Late Female Reproduction

Abstract not availabl

Headless Myo10 Is a Negative Regulator of Full-length Myo10 and Inhibits Axon Outgrowth in Cortical Neurons

Myo10 is an unconventional myosin that localizes to and induces filopodia, structures that are critical for growing axons. In addition to the ∼240-kDa full-length Myo10, brain expresses a ∼165 kDa isoform that lacks a functional motor domain and is known as headless Myo10. We and others have hypothesized that headless Myo10 acts as an endogenous dominant negative of full-length Myo10, but this hypothesis has not been tested, and the function of headless Myo10 remains unknown. We find that cortical neurons express both headless and full-length Myo10 and report the first isoform-specific localization of Myo10 in brain, which shows enrichment of headless Myo10 in regions of proliferating and migrating cells, including the embryonic ventricular zone and the postnatal rostral migratory stream. We also find that headless and full-length Myo10 are expressed in embryonic and neuronal stem cells. To directly test the function of headless and full-length Myo10, we used RNAi specific to each isoform in mouse cortical neuron cultures. Knockdown of full-length Myo10 reduces axon outgrowth, whereas knockdown of headless Myo10 increases axon outgrowth. To test whether headless Myo10 antagonizes full-length Myo10, we coexpressed both isoforms in COS-7 cells, which revealed that headless Myo10 suppresses the filopodia-inducing activity of full-length Myo10. Together, these results demonstrate that headless Myo10 can function as a negative regulator of full-length Myo10 and that the two isoforms of Myo10 have opposing roles in axon outgrowth

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