111 research outputs found
Numerical Stability of Lanczos Methods
The Lanczos algorithm for matrix tridiagonalisation suffers from strong
numerical instability in finite precision arithmetic when applied to evaluate
matrix eigenvalues. The mechanism by which this instability arises is well
documented in the literature. A recent application of the Lanczos algorithm
proposed by Bai, Fahey and Golub allows quadrature evaluation of inner products
of the form . We show that this quadrature evaluation
is numerically stable and explain how the numerical errors which are such a
fundamental element of the finite precision Lanczos tridiagonalisation
procedure are automatically and exactly compensated in the Bai, Fahey and Golub
algorithm. In the process, we shed new light on the mechanism by which roundoff
error corrupts the Lanczos procedureComment: 3 pages, Lattice 99 contributio
Macro to Nano: Scaling Effects of Bi2Te3 Thermoelectric Generators for Applications in Space
For decades research and development has been committed to improving the Figure of Merit (ZT) of Bismuth Telluride (Bi2Te3) Thermoelectric Generators (TEG) and has reached its limit at ≈1. This Meta-study aims to determine if further improvements can be made when the size of TEGs decrease. To quantify the change from macro to nano scale the change in ZT, thermal and electrical conductance, Seebeck coefficient and power factor as the size of the thermoelements decrease has been investigated as well as how Wiedemann-Franz (WF) law holds on the nanoscale. This meta-study was conducted by evaluating and comparing developments in TEGs for the past three decades. Based on theory it was expected that increases in ZT would occur as the thermoelement dimensions are reduced due to increased scattering of electrons and phonons as well as the increased density of electronic states. Increases to ZT due to these effects was not observed in experimental data due to difficulties in nanoscale production. This meta-study observed some indicators that the theory is correct in reduced thermal conduction from increased phonon and electron scattering and that phonon scattering was greater than electron scattering. Furthermore, a weak indication that WF law is not applicable on the nanoscale due to the scattering suggesting a decoupling of electrical and thermal conduction which is not achievable in macro scale TEG
Direct comparison between confocal and multiphoton microscopy for rapid histopathological evaluation of unfixed human breast tissue
Rapid histopathological examination of surgical specimen margins using fluorescence microscopy during breast conservation therapy has the potential to reduce the rate of positive margins on postoperative
histopathology and the need for repeat surgeries. To assess the suitability of imaging modalities, we perform a direct comparison between confocal fluorescence microscopy and multiphoton microscopy for imaging unfixed
tissue and compare to paraffin-embedded histology. An imaging protocol including dual channel detection of two contrast agents to implement virtual hematoxylin and eosin images is introduced that provides high quality imaging under both one and two photon excitation. Corresponding images of unfixed human breast tissue show that both confocal and multiphoton microscopy can reproduce the appearance of conventional histology without the need for physical sectioning. We further compare normal breast tissue and invasive cancer specimens imaged at multiple magnifications, and assess the effects of photobleaching for both modalities using the staining protocol. The results demonstrate that confocal fluorescence microscopy is a promising and cost-effective
alternative to multiphoton microscopy for rapid histopathological evaluation of ex vivo breast tissue.National Institutes of Health (U.S.) (Grant R01-CA178636-02)National Institutes of Health (U.S.) (Grant R01-CA075289-18)National Institutes of Health (U.S.) (Grant F32-CA183400-03)United States. Air Force. Office of Scientific Research (Grant FA9550-12-1-0551)United States. Air Force. Office of Scientific Research (Grant FA9550-15-1-0473
Design of a portable wide field of view GPU-accelerated multiphoton imaging system for real-time imaging of breast surgical specimens
We present a portable multiphoton system designed for evaluating centimeter-scale surgical margins on surgical breast specimens in a clinical setting. The system is designed to produce large field of view images at a high frame rate, while using GPU processing to render low latency, video-rate virtual H&E images for real-time assessment. The imaging system and virtual H&E rendering algorithm are demonstrated by imaging unfixed human breast tissue in a clinical setting
Emissions pathways, climate change, and impacts on California
The magnitude of future climate change depends substantially on the greenhouse gas emission pathways we choose. Here we explore the implications of the highest and lowest Intergovernmental Panel on Climate Change emissions pathways for climate change and associated impacts in California. Based on climate projections from two state-of-the-art climate models with low and medium sensitivity (Parallel Climate Model and Hadley Centre Climate Model, version 3, respectively), we find that annual temperature increases nearly double from the lower B1 to the higher A1fi emissions scenario before 2100. Three of four simulations also show greater increases in summer temperatures as compared with winter. Extreme heat and the associated impacts on a range of temperature-sensitive sectors are substantially greater under the higher emissions scenario, with some interscenario differences apparent before midcentury. By the end of the century under the B1 scenario, heatwaves and extreme heat in Los Angeles quadruple in frequency while heat-related mortality increases two to three times; alpine subalpine forests are reduced by 50–75%; and Sierra snowpack is reduced 30–70%. Under A1fi, heatwaves in Los Angeles are six to eight times more frequent, with heat-related excess mortality increasing five to seven times; alpine subalpine forests are reduced by 75–90%; and snowpack declines 73–90%, with cascading impacts on runoff and streamflow that, combined with projected modest declines in winter precipitation, could fundamentally disrupt California’s water rights system. Although interscenario differences in climate impacts and costs of adaptation emerge mainly in the second half of the century, they are strongly dependent on emissions from preceding decades
Extraordinary Biomass-Burning Episode and Impact Winter Triggered by the Younger Dryas Cosmic Impact ∼12,800 Years Ago. 2. Lake, Marine, and Terrestrial Sediments
Part 1 of this study investigated evidence of biomass burning in global ice records, and here we continue to test the
hypothesis that an impact event at the Younger Dryas boundary (YDB) caused an anomalously intense episode of
biomass burning at ∼12.8 ka on a multicontinental scale (North and South America, Europe, and Asia). Quantitative
analyses of charcoal and soot records from 152 lakes, marine cores, and terrestrial sequences reveal a major peak in
biomass burning at the Younger Dryas (YD) onset that appears to be the highest during the latest Quaternary. For the
Cretaceous-Tertiary boundary (K-Pg) impact event, concentrations of soot were previously utilized to estimate the
global amount of biomass burned, and similar measurements suggest that wildfires at the YD onset rapidly consumed
∼10 million km2 of Earth’s surface, or ∼9% of Earth’s biomass, considerably more than for the K-Pg impact. Bayesian
analyses and age regressions demonstrate that ages for YDB peaks in charcoal and soot across four continents are
synchronous with the ages of an abundance peak in platinum in the Greenland Ice Sheet Project 2 (GISP2) ice core and
of the YDB impact event (12,835–12,735 cal BP). Thus, existing evidence indicates that the YDB impact event caused
an anomalously large episode of biomass burning, resulting in extensive atmospheric soot/dust loading that triggered
an “impact winter.” This, in turn, triggered abrupt YD cooling and other climate changes, reinforced by climatic
feedback mechanisms, including Arctic sea ice expansion, rerouting of North American continental runoff, and subsequent ocean circulation changes
Sequencing of prostate cancers identifies new cancer genes, routes of progression and drug targets
Prostate cancer represents a substantial clinical challenge because it is difficult to predict outcome and advanced disease is often fatal. We sequenced the whole genomes of 112 primary and metastatic prostate cancer samples. From joint analysis of these cancers with those from previous studies (930 cancers in total), we found evidence for 22 previously unidentified putative driver genes harboring coding mutations, as well as evidence for NEAT1 and FOXA1 acting as drivers through noncoding mutations. Through the temporal dissection of aberrations, we identified driver mutations specifically associated with steps in the progression of prostate cancer, establishing, for example, loss of CHD1 and BRCA2 as early events in cancer development of ETS fusion-negative cancers. Computational chemogenomic (canSAR) analysis of prostate cancer mutations identified 11 targets of approved drugs, 7 targets of investigational drugs, and 62 targets of compounds that may be active and should be considered candidates for future clinical trials
Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans
Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have
fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in
25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16
regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of
correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP,
while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in
Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium
(LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region.
Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant
enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the
refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa,
an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of
PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent
signals within the same regio
Finishing the euchromatic sequence of the human genome
The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead
Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019
Background: In an era of shifting global agendas and expanded emphasis on non-communicable diseases and injuries along with communicable diseases, sound evidence on trends by cause at the national level is essential. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) provides a systematic scientific assessment of published, publicly available, and contributed data on incidence, prevalence, and mortality for a mutually exclusive and collectively exhaustive list of diseases and injuries. Methods: GBD estimates incidence, prevalence, mortality, years of life lost (YLLs), years lived with disability (YLDs), and disability-adjusted life-years (DALYs) due to 369 diseases and injuries, for two sexes, and for 204 countries and territories. Input data were extracted from censuses, household surveys, civil registration and vital statistics, disease registries, health service use, air pollution monitors, satellite imaging, disease notifications, and other sources. Cause-specific death rates and cause fractions were calculated using the Cause of Death Ensemble model and spatiotemporal Gaussian process regression. Cause-specific deaths were adjusted to match the total all-cause deaths calculated as part of the GBD population, fertility, and mortality estimates. Deaths were multiplied by standard life expectancy at each age to calculate YLLs. A Bayesian meta-regression modelling tool, DisMod-MR 2.1, was used to ensure consistency between incidence, prevalence, remission, excess mortality, and cause-specific mortality for most causes. Prevalence estimates were multiplied by disability weights for mutually exclusive sequelae of diseases and injuries to calculate YLDs. We considered results in the context of the Socio-demographic Index (SDI), a composite indicator of income per capita, years of schooling, and fertility rate in females younger than 25 years. Uncertainty intervals (UIs) were generated for every metric using the 25th and 975th ordered 1000 draw values of the posterior distribution. Findings: Global health has steadily improved over the past 30 years as measured by age-standardised DALY rates. After taking into account population growth and ageing, the absolute number of DALYs has remained stable. Since 2010, the pace of decline in global age-standardised DALY rates has accelerated in age groups younger than 50 years compared with the 1990–2010 time period, with the greatest annualised rate of decline occurring in the 0–9-year age group. Six infectious diseases were among the top ten causes of DALYs in children younger than 10 years in 2019: lower respiratory infections (ranked second), diarrhoeal diseases (third), malaria (fifth), meningitis (sixth), whooping cough (ninth), and sexually transmitted infections (which, in this age group, is fully accounted for by congenital syphilis; ranked tenth). In adolescents aged 10–24 years, three injury causes were among the top causes of DALYs: road injuries (ranked first), self-harm (third), and interpersonal violence (fifth). Five of the causes that were in the top ten for ages 10–24 years were also in the top ten in the 25–49-year age group: road injuries (ranked first), HIV/AIDS (second), low back pain (fourth), headache disorders (fifth), and depressive disorders (sixth). In 2019, ischaemic heart disease and stroke were the top-ranked causes of DALYs in both the 50–74-year and 75-years-and-older age groups. Since 1990, there has been a marked shift towards a greater proportion of burden due to YLDs from non-communicable diseases and injuries. In 2019, there were 11 countries where non-communicable disease and injury YLDs constituted more than half of all disease burden. Decreases in age-standardised DALY rates have accelerated over the past decade in countries at the lower end of the SDI range, while improvements have started to stagnate or even reverse in countries with higher SDI. Interpretation: As disability becomes an increasingly large component of disease burden and a larger component of health expenditure, greater research and developm nt investment is needed to identify new, more effective intervention strategies. With a rapidly ageing global population, the demands on health services to deal with disabling outcomes, which increase with age, will require policy makers to anticipate these changes. The mix of universal and more geographically specific influences on health reinforces the need for regular reporting on population health in detail and by underlying cause to help decision makers to identify success stories of disease control to emulate, as well as opportunities to improve. Funding: Bill & Melinda Gates Foundation. © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 licens
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