Multiplex analysis of mitochondrial DNA pathogenic and polymorphic sequence variants

The mitochondrial DNA (mtDNA) encompasses two classes of functionally important sequence variants: recent pathogenic mutations and ancient adaptive polymorphisms. To rapidly and cheaply evaluate both classes of single nucleotide variants (SNVs), we have developed an integrated system in which mtDNA SNVs are analyzed by multiplex primer extension using the SNaPshot system. A multiplex PCR amplification strategy was used to amplify the entire mtDNA, a computer program identifies optimal extension primers, and a complete global haplotyping system is also proposed. This system genotypes SNVs on multiplexed mtDNA PCR products or directly from enriched mtDNA samples and can quantify heteroplasmic variants down to 0.8% using a standard curve. With this system, we have developed assays for testing the common pathogenic mutations in four multiplex panels: two genotype the 13 most common pathogenic mtDNA mutations and two genotype the 10 most common Leber Hereditary Optic Neuropathy mutations along with haplogroups J and T. We use a hierarchal system of 140 SNVs to delineate the major global mtDNA haplogroups based on a global phylogenetic tree of coding region polymorphisms. This system should permit rapid and inexpensive genotyping of pathogenic and lineage-specific mtDNA SNVs by clinical and research laboratories

Low- and High-Drag Intermittencies in Turbulent Channel Flows

Recent direct numerical simulations (DNS) and experiments in turbulent channel flow have found intermittent low- and high-drag events in Newtonian fluid flows, at Reτ=uτh/ν between 70 and 100, where uτ, h and ν are the friction velocity, channel half-height and kinematic viscosity, respectively. These intervals of low-drag and high-drag have been termed “hibernating” and “hyperactive”, respectively, and in this paper, a further investigation of these intermittent events is conducted using experimental and numerical techniques. For experiments, simultaneous measurements of wall shear stress and velocity are carried out in a channel flow facility using hot-film anemometry (HFA) and laser Doppler velocimetry (LDV), respectively, for Reτ between 70 and 250. For numerical simulations, DNS of a channel flow is performed in an extended domain at Reτ = 70 and 85. These intermittent events are selected by carrying out conditional sampling of the wall shear stress data based on a combined threshold magnitude and time-duration criteria. The use of three different scalings (so-called outer, inner and mixed) for the time-duration criterion for the conditional events is explored. It is found that if the time-duration criterion is kept constant in inner units, the frequency of occurrence of these conditional events remain insensitive to Reynolds number. There exists an exponential distribution of frequency of occurrence of the conditional events with respect to their duration, implying a potentially memoryless process. An explanation for the presence of a spike (or dip) in the ensemble-averaged wall shear stress data before and after the low-drag (or high-drag) events is investigated. During the low-drag events, the conditionally-averaged streamwise velocities get closer to Virk’s maximum drag reduction (MDR) asymptote, near the wall, for all Reynolds numbers studied. Reynolds shear stress (RSS) characteristics during these conditional events are investigated for Reτ = 70 and 85. Except very close to the wall, the conditionally-averaged RSS is higher than the time-averaged value during the low-drag events.</jats:p

Small-Scale Vertical Movements of Summer Flounder Relative to Diurnal, Tidal, and Temperature Changes

Observation of animal movements on small spatial scales provides a means to understand how large-scale species distributions are established from individual behavioral decisions. Small-scale vertical movements of 14 Summer Flounder Paralichthys dentatus residing in Chesapeake Bay were observed by using depth data collected with archival tags. A generalized linear mixed model was employed to examine the relationship between these vertical movements and environmental covariates such as tidal state, time of day, lunar phase, and temperature. Vertical movements increased with warming water temperatures, and this pattern was most apparent at night and during rising and falling tides. Fish generally exhibited greater vertical movements at night, but the difference between vertical movements in the day and those at night decreased as fish increased in size. Results from this study fill a void in understanding the small-scale movements of Summer Flounder and could be incorporated into individual-based models to investigate how species distributions develop in response to environmental conditions

[Accepted Manuscript] Presymptomatic atrophy in autosomal dominant Alzheimer's disease: A serial MRI study.

Identifying at what point atrophy rates first change in Alzheimer's disease is important for informing design of presymptomatic trials. Serial T1-weighed magnetic resonance imaging scans of 94 participants (28 noncarriers, 66 carriers) from the Dominantly Inherited Alzheimer Network were used to measure brain, ventricular, and hippocampal atrophy rates. For each structure, nonlinear mixed-effects models estimated the change-points when atrophy rates deviate from normal and the rates of change before and after this point. Atrophy increased after the change-point, which occurred 1-1.5 years (assuming a single step change in atrophy rate) or 3-8 years (assuming gradual acceleration of atrophy) before expected symptom onset. At expected symptom onset, estimated atrophy rates were at least 3.6 times than those before the change-point. Atrophy rates are pathologically increased up to seven years before &quot;expected onset&quot;. During this period, atrophy rates may be useful for inclusion and tracking of disease progression

Global surveillance of cancer survival 1995-2009: analysis of individual data for 25,676,887 patients from 279 population-based registries in 67 countries (CONCORD-2)

BACKGROUND: Worldwide data for cancer survival are scarce. We aimed to initiate worldwide surveillance of cancer survival by central analysis of population-based registry data, as a metric of the effectiveness of health systems, and to inform global policy on cancer control. METHODS: Individual tumour records were submitted by 279 population-based cancer registries in 67 countries for 25·7 million adults (age 15-99 years) and 75,000 children (age 0-14 years) diagnosed with cancer during 1995-2009 and followed up to Dec 31, 2009, or later. We looked at cancers of the stomach, colon, rectum, liver, lung, breast (women), cervix, ovary, and prostate in adults, and adult and childhood leukaemia. Standardised quality control procedures were applied; errors were corrected by the registry concerned. We estimated 5-year net survival, adjusted for background mortality in every country or region by age (single year), sex, and calendar year, and by race or ethnic origin in some countries. Estimates were age-standardised with the International Cancer Survival Standard weights. FINDINGS: 5-year survival from colon, rectal, and breast cancers has increased steadily in most developed countries. For patients diagnosed during 2005-09, survival for colon and rectal cancer reached 60% or more in 22 countries around the world; for breast cancer, 5-year survival rose to 85% or higher in 17 countries worldwide. Liver and lung cancer remain lethal in all nations: for both cancers, 5-year survival is below 20% everywhere in Europe, in the range 15-19% in North America, and as low as 7-9% in Mongolia and Thailand. Striking rises in 5-year survival from prostate cancer have occurred in many countries: survival rose by 10-20% between 1995-99 and 2005-09 in 22 countries in South America, Asia, and Europe, but survival still varies widely around the world, from less than 60% in Bulgaria and Thailand to 95% or more in Brazil, Puerto Rico, and the USA. For cervical cancer, national estimates of 5-year survival range from less than 50% to more than 70%; regional variations are much wider, and improvements between 1995-99 and 2005-09 have generally been slight. For women diagnosed with ovarian cancer in 2005-09, 5-year survival was 40% or higher only in Ecuador, the USA, and 17 countries in Asia and Europe. 5-year survival for stomach cancer in 2005-09 was high (54-58%) in Japan and South Korea, compared with less than 40% in other countries. By contrast, 5-year survival from adult leukaemia in Japan and South Korea (18-23%) is lower than in most other countries. 5-year survival from childhood acute lymphoblastic leukaemia is less than 60% in several countries, but as high as 90% in Canada and four European countries, which suggests major deficiencies in the management of a largely curable disease. INTERPRETATION: International comparison of survival trends reveals very wide differences that are likely to be attributable to differences in access to early diagnosis and optimum treatment. Continuous worldwide surveillance of cancer survival should become an indispensable source of information for cancer patients and researchers and a stimulus for politicians to improve health policy and health-care systems

Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus

A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk

Track A Basic Science

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/138319/1/jia218438.pd

MATISSE, the VLTI mid-infrared imaging spectro-interferometer

GalaxiesStars and planetary systemsInstrumentatio