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 ∘^\circC

Non-volatile memory (NVM) devices that reliably operate at temperatures above 300 $^\circ$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 Al$_x$Sc$_{1-x}$N exhibits strong potential for utilization in NVM devices operating at very high temperatures (> 500 $^\circ$C) given its stable and high remnant polarization (PR) above 100 $\mu$C/cm$^2$ with demonstrated ferroelectric transition temperature (TC) > 1000 $^\circ$C. Here, we demonstrate an Al$_{0.68}$Sc$_{0.32}$N ferroelectric diode based NVM device that can reliably operate with clear ferroelectric switching up to 600 $^\circ$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 $^\circ$C. The devices exhibit high remnant polarizations (> 100 $\mu$C/cm$^2$) which are stable at high temperatures. At 500 $^\circ$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 $^\circ$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

JINGLE, a JCMT legacy survey of dust and gas for galaxy evolution studies: II. SCUBA-2 850 μm data reduction and dust flux density catalogues

We present the SCUBA-2 850μm component of JINGLE, the new JCMT large survey for dust and gas in nearby galaxies, which with 193 galaxies is the largest targeted survey of nearby galaxies at 850 μm. We provide details of our SCUBA-2 data reduction pipeline, optimized for slightly extended sources, and including a calibration model adjusted to match conventions used in other far-infrared (FIR) data. We measure total integrated fluxes for the entire JINGLE sample in 10 infrared/submillimetre bands, including all WISE, Herschel-PACS, Herschel-SPIRE, and SCUBA-2 850 μm maps, statistically accounting for the contamination by CO(J = 3-2) in the 850 μm band. Of our initial sample of 193 galaxies, 191 are detected at 250 μm with a ≥5σ significance. In the SCUBA-2 850 μm band we detect 126 galaxies with ≥3σ significance. The distribution of the JINGLE galaxies in FIR/sub-millimetre colour-colour plots reveals that the sample is not well fit by single modified-blackbody models that assume a single dust-emissivity index (β). Instead, our new 850 μm data suggest either that a large fraction of our objects require β < 1.5, or that a model allowing for an excess of sub-mm emission (e.g. a broken dust emissivity law, or a very cold dust component ≲10 K) is required. We provide relations to convert FIR colours to dust temperature and β for JINGLE-like galaxies. For JINGLE the FIR colours correlate more strongly with star-formation rate surface-density rather than the stellar surface-density, suggesting heating of dust is greater due to younger rather than older stellar-populations, consistent with the low proportion of early-type galaxies in the sample