784 research outputs found
Modelling, inference and big data in biophysics
Letter to the editorIn recognition of the increasing importance of big data in biophysics, a new session called 'Modelling, inference, big data' is incorporated into the IUPAB/EBSA Congress on 18 July 2017 at Edinburgh, UK
Testing and Validating Machine Learning Classifiers by Metamorphic Testing
Machine Learning algorithms have provided important core functionality to support solutions in many scientific computing applications - such as computational biology, computational linguistics, and others. However, it is difficult to test such applications because often there is no "test oracle" to indicate what the correct output should be for arbitrary input. To help address the quality of scientific computing software, in this paper we present a technique for testing the implementations of machine learning classification algorithms on which such scientific computing software depends. Our technique is based on an approach called "metamorphic testing", which has been shown to be effective in such cases. Also presented is a case study on a real-world machine learning application framework, and a discussion of how programmers implementing machine learning algorithms can avoid the common pitfalls discovered in our study. We also conduct mutation analysis and cross-validation, which reveal that our method has very high effectiveness in killing mutants, and that observing expected cross-validation result alone is not sufficient to test for the correctness of a supervised classification program. Metamorphic testing is strongly recommended as a complementary approach. Finally we discuss how our findings can be used in other areas of computational science and engineering
Drug-associated changes in amino acid residues in Gag p2, p7NC, and p6Gag/p6Pol in human immunodeficiency virus type 1 (HIV-1) display a dominant effect on replicative fitness and drug response
AbstractRegions of HIV-1 gag between p2 and p6Gag/p6Pol, in addition to protease (PR), develop genetic diversity in HIV-1 infected individuals who fail to suppress virus replication by combination protease inhibitor (PI) therapy. To elucidate functional consequences for viral replication and PI susceptibility by changes in Gag that evolve in vivo during PI therapy, a panel of recombinant viruses was constructed. Residues in Gag p2/p7NC cleavage site and p7NC, combined with residues in the flap of PR, defined novel fitness determinants that restored replicative capacity to the posttherapy virus. Multiple determinants in Gag have a dominant effect on PR phenotype and increase susceptibility to inhibitors of drug-resistant or drug-sensitive PR genes. Gag determinants of drug sensitivity and replication alter the fitness landscape of the virus, and viral replicative capacity can be independent of drug sensitivity. The functional linkage between Gag and PR provides targets for novel therapeutics to inhibit drug-resistant viruses
A dynamic H3K27ac signature identifies VEGFA-stimulated endothelial enhancers and requires EP300 activity
Histone modifications are now well-established mediators of transcriptional programs that distinguish cell states. However, the kinetics of histone modification and their role in mediating rapid, signal-responsive gene expression changes has been little studied on a genome-wide scale. Vascular endothelial growth factor A (VEGFA), a major regulator of angiogenesis, triggers changes in transcriptional activity of human umbilical vein endothelial cells (HUVECs). Here, we used chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq) to measure genome-wide changes in histone H3 acetylation at lysine 27 (H3K27ac), a marker of active enhancers, in unstimulated HUVECs and HUVECs stimulated with VEGFA for 1, 4, and 12 h. We show that sites with the greatest H3K27ac change upon stimulation were associated tightly with EP300, a histone acetyltransferase. Using the variation of H3K27ac as a novel epigenetic signature, we identified transcriptional regulatory elements that are functionally linked to angiogenesis, participate in rapid VEGFA-stimulated changes in chromatin conformation, and mediate VEGFA-induced transcriptional responses. Dynamic H3K27ac deposition and associated changes in chromatin conformation required EP300 activity instead of altered nucleosome occupancy or changes in DNase I hypersensitivity. EP300 activity was also required for a subset of dynamic H3K27ac sites to loop into proximity of promoters. Our study identified thousands of endothelial, VEGFA-responsive enhancers, demonstrating that an epigenetic signature based on the variation of a chromatin feature is a productive approach to define signal-responsive genomic elements. Further, our study implicates global epigenetic modifications in rapid, signal-responsive transcriptional regulation
Burst mitofusin activation reverses neuromuscular dysfunction in murine CMT2A
Charcot-Marie-Tooth disease type 2A (CMT2A) is an untreatable childhood peripheral neuropathy caused by mutations of the mitochondrial fusion protein, mitofusin (MFN) 2. Here, pharmacological activation of endogenous normal mitofusins overcame dominant inhibitory effects of CMT2A mutants in reprogrammed human patient motor neurons, reversing hallmark mitochondrial stasis and fragmentation independent of causa
Scalable and Stable Ferroelectric Non-Volatile Memory at > 500 C
Non-volatile memory (NVM) devices that reliably operate at temperatures above
300 C are currently non-existent and remains a critically unmet
challenge in the development of high-temperature (T) resilient electronics,
necessary for many emerging, complex computing and sensing in harsh
environments. Ferroelectric AlScN exhibits strong potential for
utilization in NVM devices operating at very high temperatures (> 500
C) given its stable and high remnant polarization (PR) above 100
C/cm with demonstrated ferroelectric transition temperature (TC) >
1000 C. Here, we demonstrate an AlScN ferroelectric
diode based NVM device that can reliably operate with clear ferroelectric
switching up to 600 C with distinguishable On and Off states. The
coercive field (EC) from the Pulsed I-V measurements is found to be -5.84 (EC-)
and +5.98 (EC+) (+/- 0.1) MV/cm at room temperature (RT) and found to decrease
with increasing temperature up to 600 C. The devices exhibit high
remnant polarizations (> 100 C/cm) which are stable at high
temperatures. At 500 C, our devices show 1 million read cycles and
stable On-Off ratio above 1 for > 6 hours. Finally, the operating voltages of
our AlScN ferrodiodes are < 15 V at 600 C which is well matched and
compatible with Silicon Carbide (SiC) based high temperature logic technology,
thereby making our demonstration a major step towards commercialization of NVM
integrated high-T computers.Comment: MS and S
Hepcidin sequesters iron to sustain nucleotide metabolism and mitochondrial function in colorectal cancer epithelial cells
Colorectal cancer (CRC) requires massive iron stores, but the complete mechanisms by which CRC modulates local iron handling are poorly understood. Here, we demonstrate that hepcidin is activated ectopically in CRC. Mice deficient in hepcidin specifically in the colon tumour epithelium, compared with wild-type littermates, exhibit significantly diminished tumour number, burden and size in a sporadic model of CRC, whereas accumulation of intracellular iron by deletion of the iron exporter ferroportin exacerbates these tumour parameters. Metabolomic analysis of three-dimensional patient-derived CRC tumour enteroids indicates a prioritization of iron in CRC for the production of nucleotides, which is recapitulated in our hepcidin/ferroportin mouse CRC models. Mechanistically, our data suggest that iron chelation decreases mitochondrial function, thereby altering nucleotide synthesis, whereas exogenous supplementation of nucleosides or aspartate partially rescues tumour growth in patient-derived enteroids and CRC cell lines in the presence of an iron chelator. Collectively, these data suggest that ectopic hepcidin in the tumour epithelium establishes an axis to sequester iron in order to maintain the nucleotide pool and sustain proliferation in colorectal tumours
JINGLE, a JCMT legacy survey of dust and gas for galaxy evolution studies - I. Survey overview and first results
JINGLE is a new JCMT legacy survey designed to systematically study the cold interstellar medium of galaxies in the local Universe. As part of the survey we perform 850 μm continuum measurements with SCUBA-2 for a representative sample of 193 Herschel-selected galaxies with M* \u3e 109 M⊙, as well as integrated CO(2-1) line fluxes with RxA3m for a subset of 90 of these galaxies. The sample is selected from fields covered by the Herschel-ATLAS survey that are also targeted by the MaNGA optical integral-field spectroscopic survey. The new JCMT observations combined with the multiwavelength ancillary data will allow for the robust characterization of the properties of dust in the nearby Universe, and the benchmarking of scaling relations between dust, gas, and global galaxy properties. In this paper we give an overview of the survey objectives and details about the sample selection and JCMT observations, present a consistent 30-band UV-to-FIR photometric catalogue with derived properties, and introduce the JINGLE Main Data Release. Science highlights include the non-linearity of the relation between 850 μm luminosity and CO line luminosity (log LCO(2-1) = 1.372 logL850-1.376), and the serendipitous discovery of candidate z \u3e 6 galaxies
The Ninth Data Release of the Sloan Digital Sky Survey: First Spectroscopic Data from the SDSS-III Baryon Oscillation Spectroscopic Survey
The Sloan Digital Sky Survey III (SDSS-III) presents the first spectroscopic
data from the Baryon Oscillation Spectroscopic Survey (BOSS). This ninth data
release (DR9) of the SDSS project includes 535,995 new galaxy spectra (median
z=0.52), 102,100 new quasar spectra (median z=2.32), and 90,897 new stellar
spectra, along with the data presented in previous data releases. These spectra
were obtained with the new BOSS spectrograph and were taken between 2009
December and 2011 July. In addition, the stellar parameters pipeline, which
determines radial velocities, surface temperatures, surface gravities, and
metallicities of stars, has been updated and refined with improvements in
temperature estimates for stars with T_eff<5000 K and in metallicity estimates
for stars with [Fe/H]>-0.5. DR9 includes new stellar parameters for all stars
presented in DR8, including stars from SDSS-I and II, as well as those observed
as part of the SDSS-III Sloan Extension for Galactic Understanding and
Exploration-2 (SEGUE-2).
The astrometry error introduced in the DR8 imaging catalogs has been
corrected in the DR9 data products. The next data release for SDSS-III will be
in Summer 2013, which will present the first data from the Apache Point
Observatory Galactic Evolution Experiment (APOGEE) along with another year of
data from BOSS, followed by the final SDSS-III data release in December 2014.Comment: 9 figures; 2 tables. Submitted to ApJS. DR9 is available at
http://www.sdss3.org/dr
Hotspot SF3B1 mutations induce metabolic reprogramming and vulnerability to serine deprivation.
Cancer-associated mutations in the spliceosome gene SF3B1 create a neomorphic protein that produces aberrant mRNA splicing in hundreds of genes, but the ensuing biologic and therapeutic consequences of this missplicing are not well understood. Here we have provided evidence that aberrant splicing by mutant SF3B1 altered the transcriptome, proteome, and metabolome of human cells, leading to missplicing-associated downregulation of metabolic genes, decreased mitochondrial respiration, and suppression of the serine synthesis pathway. We also found that mutant SF3B1 induces vulnerability to deprivation of the nonessential amino acid serine, which was mediated by missplicing-associated downregulation of the serine synthesis pathway enzyme PHGDH. This vulnerability was manifest both in vitro and in vivo, as dietary restriction of serine and glycine in mice was able to inhibit the growth of SF3B1MUT xenografts. These findings describe a role for SF3B1 mutations in altered energy metabolism, and they offer a new therapeutic strategy against SF3B1MUT cancers
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